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Review

The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma

by
Xue Jiang
1,†,
Hor-Yue Tan
2,†,
Shanshan Teng
1,
Yau-Tuen Chan
2,
Di Wang
1,* and
Ning Wang
2,*
1
School of Life Sciences, Jilin University, Changchun 130012, China
2
School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2019, 11(5), 647; https://doi.org/10.3390/cancers11050647
Submission received: 22 March 2019 / Revised: 6 May 2019 / Accepted: 7 May 2019 / Published: 10 May 2019
(This article belongs to the Special Issue Hepatocellular Cancer Treatment)
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Abstract

:
Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of HCC treatment. AMP-Activated Protein Kinase (AMPK) is an essential intracellular energy sensor that plays multiple roles in cellular physiology and the pathological development of chronic diseases. Recent studies have highlighted the important regulation of AMPK in HCC. This review aims to comprehensively and critically summarize the role of AMPK in HCC. Methods: Original studies were retrieved from NCBI database with keywords including AMPK and HCC, which were analyzed with extensive reading. Results: Dysregulation of the kinase activity and expression of AMPK was observed in HCC, which was correlated with survival of the patients. Loss of AMPK in HCC cells may proceed cell cycle progression, proliferation, survival, migration, and invasion through different oncogenic molecules and pathways. Conclusions: We identified several AMPK activators which may possess potential anti-HCC function, and discussed the clinical perspective on the use of AMPK activators for HCC therapy.

1. Introduction

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer all over the world and accounts for more than 85% of liver malignancies [1]. It is more prevalent in developing countries, within which China accounts for over 50% of the world’s newly diagnosed cases as well as HCC-related death annually [2,3]. Typically, HCC progression is triggered by nonalcoholic fatty liver disease (NAFLD), long-term exposure to aflatoxin and alcohol, or chronic infection with hepatitis B and C [4]. Epidemiological studies have revealed that the risk factors of HCC in developing countries are Hepatitis B virus (HBV) infection and aflatoxin exposure, while it is Hepatitis C virus (HCV) and alcohol in developed countries [5]. Primary curative treatments for patients with HCC are surgical resection and liver transplantation [6]. Due to the unfavorable hepatic condition in most of the patients with HCC, only around 30% of patients are suitable for surgery. The high recurrence rate of HCC resulted in poor prognosis even in patients with the hepatic operation. The 5-year overall survival rate of patients with HCC after surgery are less than 30% [7]. Non-surgical treatment is often ineffective, as the HCC cells are naturally resistant to most of the conventional chemotherapeutic agents [8,9]. Several targets therapeutic agents have been approved for HCC treatment, such as sorafenib, lenvatinib and regorafenib [6]; however, the improvement on the overall survival of patients with HCC is still limited. For example, sorafenib was shown to add around three months to the survival of patients with HCC in western countries, but only 2.3 months in patients in the Asian-Pacific region [10,11]. Identification of novel therapeutic targets of HCC for next-generation drug discovery and development is necessary and pressing.
AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric serine/threonine kinase, serves as a eukaryotic cellular energy sensor and plays a vital role in the coordination of cell growth and metabolism. Under physiological condition, AMPK is regarded as a highly sensitive safeguard that responds to the changes in ATP production. Even with modest decreases in ATP production, AMPK could promote catabolic pathways to generate more ATP, and suppress anabolic signaling [12]. In mammals, AMPK has been shown to play essential roles in metabolic regulation in specialized tissues including liver, muscle, and fat [13]. In some pathological circumstances such as ischemia, hypoxia, low glucose level, or heat shock, AMPK is activated by an increased ratio of cellular AMP/ATP or ADP/ATP, and coordinates a series of cellular process including autophagy, apoptosis, cell cycle, cell metabolism as well as protein synthesis [14]. Malfunction and dysregulation of AMPK have been observed even different types of diseases, such as obesity [15], diabetes [16], aging [17], hypertension [18], heart failure [19], hepatic diseases [20] and certain types of cancers [21,22]. In particular, a growing body of research findings suggested that AMPK dysfunction may mediate a series of essential processes during the carcinogenesis and HCC progression. In this review, we critically summarized the recent findings identifying the role of AMPK in HCC. We also envisioned HCC treatment targeting AMPK according to the current understanding of the action AMPK activators. We hope our summary and discussion would shed light on the potential of AMPK as a therapeutic target in HCC treatment.

2. Structure and the Activation of AMPK

AMPK is a kind of heterotrimeric protein composed of a catalytic α subunit and two regulatory β and γ subunits [23]. Each of the subunits has two or three isoforms (α1 and α2; β1 and β2; γ1, γ2 and γ3) that are encoded by different genes [24]. The α subunit has a serine/threonine kinase structural domain as the principal regulatory site of AMPK activity and contains a central threonine activating site modulated by the upstream kinases [25]. The β subunit is thought to be the scaffold for α and γ subunits [26]. There are three AMP-binding domains in the γ subunit, one links with nucleotide and the other two links with ATP or AMP [26]. Moreover, the non-exchangeable nucleotide-binding sites include four repeats of a sequence motif named Cystathionine Beta Synthase (CBS) repeat [27].
Three complementary mechanisms have been hypothesized in the activation of AMPK. First, the binding of AMP to the γ subunit leads to the allosteric activation of AMPK, and the increasing rate of the intracellular AMP:ATP motivates the substitution of ATP with AMP at the two exchangeable sites in the γ subunit. Second, the α subunit is phosphorylated in residue Thr172 by upstream kinases like Ca2+/calmodulin-dependent protein kinase β (CaMKKβ) and LKB1 [28,29]. Last but not least, the protein phosphatases (PP2A, PP2C) lead to the dephosphorylation of Thr172, which can be inhibited by AMP binding to AMPK [30]. Hence, the significant AMPK determinants activity are conformational switch induced by AMP and the α subunit phosphorylation on Thr172 (Figure 1). A series of reviews have reported the downstream signal pathways involving AMPK activity such as mitochondrial biogenesis, autophagy and inflammation response, as well summarized in other reviews [25,31,32]. Some downstream signal pathways of AMPK are shown in Figure 1.

3. Dysregulation of AMPK in HCC

It has always been reported that AMPK was aberrantly regulated during the carcinogenesis and progression of HCC, which was correlated with the aggressive clinicopathologic features and poor prognosis [14]. Cytokines in the tumor microenvironment may regulate AMPK expression and activity in HCC. CXCL17, a novel chemokine consisted of 119 amino acids, was found to suppress AMPK activity [33]. Yang et al. [34] analyzed the phosphorylation status of AMPK at Thr172 in the liver tissue of patients with cirrhosis. With 87-month follow-up, it was found that patients with low AMPK phosphorylation had a significantly higher incidence of HCC than patients with high AMPK phosphorylation levels (3.1/9.6/13.8/30.6% vs. 0/0.3/0.3/8% at 1/3/5/10 years after Hassab procedure; p < 0.001). Patients with p-AMPK low expression were estimated with a significantly higher risk of HCC occurrence in univariable analysis (Hazard ratio (HR), 6.25; 95% Confidence interval (CI): 3.36–11.60; p < 0.001) and multivariable analysis (HR, 6.0; 95% CI: 3.24–11.10; p < 0.001) [34]. In a cohort of 273 HCC patients including 253 with HBV history, low level of AMPK phosphorylation was found in 61.8% (81/131) of the patients. Low p-AMPK expression in HCC was correlated with high-serum α-fetoprotein (AFP) level, incomplete tumor encapsulation, late tumor–node–metastasis (TNM) stage, portal venous invasion, and distant metastasis [14]. In HCC patient receiving transcatheter arterial chemoembolization (TACE), the higher phosphorylation level of AMPK at Thr172 predicted improved disease-free and overall survival in a cohort of 378 Chinese HCC patients, while lower Thr172 phosphorylation indicated the presence of tumor-initiating cells in the liver [35]. Cai et al. analyzed the aberrantly methylated-differentially expressed genes in the Gene ominous database (https://www.ncbi.nlm.nih.gov/gds) of human HCC and found that genes enriched in AMPK pathways were significantly hypermethylated in HCC [36]. Divergent processes have been reported to attribute to AMPK down-regulation in HCC. Ketone catabolism in HCC cells was critical for the repression of AMPK activity under nutrient deprivation conditions [37]. The significant correlation between high SIRT1 activation and Thr172 phosphorylation of AMPK was found in HCC tissue harboring mutated p53 (p = 0.003, n = 57). Moreover, inactivation of SIRT1 was showed to inhibit AMPK pathway in HCC cells [38]. Oncogenic Ser/Thr protein phosphatase 5 (PP5) was also responsible for the decreased phosphorylated AMPK during hepatocarcinogenesis [39]. PP5 Inhibition reactivated AMPK signaling and suppressed HCC growth [40]. Deregulation of AMPK pathways in HCC may therefore play important role in cancer cell proliferation, survival, migration, invasion and metabolism (as summarized in Table S1).

4. The Regulation of AMPK on HCC

4.1. Regulation on Cell Proliferation

In HCC tissues, AMPK activity was negatively correlated with the tumor proliferation marker Ki67 [41], suggesting a role of AMPK in regulating HCC cell proliferation. Diverse mechanisms and signaling transductions have been investigated. Cell proliferation of mammalian HCC is commanded by the cell cycle progression, which is strictly regulated by the balance between cyclin-dependent kinases (CDKs), CDK inhibitors (CDKIs) and other growth suppressor proteins (GSPs) like p53 [42]. AMPK activation was found to induce G1/S phase cell cycle arrest of HCC cells, which was related to the increased expression of p27 and phosphorylation of Rb in HCC cells [43]. Another study on different HCC cell lines showed consistent G1/S arrest upon AMPK activation; however, this action of AMPK was most probably related to the up-regulation of p21 but not p27 [44]. Mechanistically, activation of AMPK triggered the phosphorylation of its downstream acetyl-CoA carboxylase carboxylase (ACC) to inhibit cell cycle regulators cyclin D1, CDK4 and CDK6 expression [45,46].
Other pathways are also involved in the regulation of AMPK on HCC cell proliferation. AMPK activation suppressed the transcription factor Sp1, which was responsible for the expression of DNMT1. DNMT1 silencing resulted in the reactivation of tumor suppressor genes and inhibited tumor growth [47,48,49]. β-catenin is a main oncogenic driver in HCC, which can regulate various of genes participant in cell development, growth, differentiation, and metastasis. The interaction between β-catenin and AMPK can regulate the proliferation and survival of HCC cells with selenium treatment [50,51]. AMPK activation blunted the protein translation-related mTOR signaling [52]. Other proliferation-related signaling that could be regulated by AMPK in HCC including ACC, p53 [53] and nuclear factor kappa-B (NF-κB) signaling [14].
YAP/TAZ is found as an attractive therapeutic target in HCC. The YAP/TAZ signaling modulator, NUAK2, also named as sucrose nonfermenting (SNF1)-like kinase (SNARK), is one of the AMPK-related kinases [54]. NUAK2 was identified as a key mediator of YAP-driven tumorigenesis and hepatomegaly in liver cancer models, whose pharmacological inactivation inhibited YAP-dependent liver overgrowth and cancer cell proliferation [55]. By promoting TGF-β signaling pathway, SNARK was reported to be a profibrogenic factor in HCC cells [56]. An anti-alcoholism drug disulfiram inhibited SNARK-promoted TGF-β signaling and exhibited anti-HCC effects [57].

4.2. Regulation on Cell Death

Hepatoma cells had LKB1 defects that blunted the AMPK signaling, and therefore were resistant to apoptosis induced by adenosine 3′,5′-cyclic monophosphate activation of protein kinase A and calcium/calmodulin-dependent protein kinase 2 [58]. This could be further proven with the evidence of inhibition of LKB1-downstream mTOR by AMPK activation [59], which initiated proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-related HCC cell apoptosis [60]. Another study suggested that peroxisome proliferator-activated receptor γ (PPARγ) signaling could be activated by AMPK signaling, which was attributed to the increasing cell apoptosis [61]. Activation of AMPK in HCC was found to be associated with mitochondrial dysfunction and subsequent cell apoptosis [45,62]. This could be related to the endoplasmic reticulum stress and loss of mitochondrial membrane potential [63], which in turn activated the caspases cascades [64]. AMPK activation in HCC cells could also inactivate SIRT1, the p53 deacetylase to promote p53 acetylation and activation. [53,65]. In contrast, it was found that AMPK activation in HBV-related HCC cells could induce MnSOD expression, the enzyme that relieves intracellular redox stress and alleviates HCC cell apoptosis [66].
It was also suggested that AMPK activation in HCC resulted in transcription factor CCAAT/enhancer-binding protein delta (CEBPD) activation, which contributed to LC3B expression and induced autophagic cell death [67]. Another study suggested that the AMPK-induced autophagic cell death in HCC was dependent on the mTOR inhibition [68]. Interestingly, AMPK-induced autophagy in HCC was found to be linked with apoptotic cell death. Autophagy seemed to be necessary for the apoptosis initiation in HCC cells upon AMPK activation [69]. A further mechanistic study showed that the AMPK-induced autophagy was responsible for the lysosomal degradation of XIAP, the endogenous inhibitor of apoptosis, and promoted apoptotic cell death [70]. These findings suggested that both apoptosis and autophagy cooperatively contributed to the cell death of HCC upon AMPK activation.

4.3. Regulation on Cell Invasion and Metastasis

The reduced level of AMPK in HCC cells resulted in a new energy stress-inducible lncRNA MITA1, which in turn promoted Slug expression and epithelial-mesenchymal transition, the critical step of cancer metastasis [71]. AMPK suppression led to mTOR activation, which subsequently induced S6K/S6 signaling to promote cell motility [72]. Activation of AMPK was found to mediate the inhibition of HCC cell motility and invasiveness [73], as well as its adhesion to blood vessels [74]. AMPK activation suppressed Sp1 transcription factor, which was responsible for the invasion-related gene DNMT1 expression [47]. AMPK was also found to suppress JNK phosphorylation and Nanog expression induced by basic fibroblast growth factor (bFGF) in metastatic HCC cells [75].

4.4. Regulation of Cancer Metabolism

AMPK as a cell-intrinsic metabolic sensor can coordinate various metabolic process during the hepatocarcinogenesis and progression of HCC. MATα1:MATα2 switch in the liver human repressed AMPK signaling to deregulate the methionine metabolism [76]. Further study showed that AMPK was essential to suppress the NF-κB activation and signal transducer and activator of transcription 3 (STAT3) in response to metabolic stress during hepatocarcinogenesis, and prevented the dysregulation of glycogen storage and formation of the hepatic tumor [77]. HCC cells could also re-activate ketone catabolism, which repressed AMPK activity and protected tumor cells from excessive autophagic cell death [37]. In addition to its well-known effect in regulating glucose metabolism, AMPK was reported to participate in the regulation on the metabolism of cellular fatty acid and protein. Mice with functional loss of mutation on AMPK showed accelerated de novo lipogenesis and formation of the liver lesion [78]. AMPK activation mediated the inhibition of nascent protein synthesis and retarded HCC proliferation [79]. However, in HBV-associated carcinogenesis of HCC, AMPK activation was proposed to have a tumor-promoting role. HBX protein induced a hyperactivation of AMPK and its downstream signaling, which re-directed the metabolic pathway in hepatocytes to facilitate persistent HBV replication. AMPK inhibition showed to reduce HBV DNA replication [80]. Further study showed that HBX-activated AMPK could initiate calcium/CaMKK-dependent pathway-dependent fatty acid oxidation to maintain the cellular NADPH and ATP level for HBV replication [80].

5. AMPK Activators in HCC Treatment

Indirect and direct activators of AMPK have been discovered and developed. Direct activators of AMPK require an interaction between the compounds and the protein, leading to the conformational change of AMPK. Most of the direct AMPK activators are the chemical analogs of AMP or ADP. Indirect activators of AMPK can be practically any modulators of AMP or calcium concentration, which allows the interaction between the compound and AMPK protein not necessary [81]. Several AMPK activators have been extensively studied for their anti-HCC activities, including indirect activators metformin and berberine, and direct activators 5-aminoimidazole-4-carboxamide riboside (AICAR), thienopyridone (A-769662) and benzimidazole (compound 911) derivatives (Figure 2).

5.1. Metformin

In AKT/c-Met-triggered HCC mice models, metformin obstructed the malignant transformation of hepatocytes and consequently delayed HCC initiation [82]. This was related to the reduced p-Erk and expression of oncogenic Cyclin D1 and c-Myc, as well as the suppression of fatty acid synthase-induced de novo lipogenesis and ATP production.
In vitro study confirmed that the action of metformin was AMPK- and SREBP1c-dependent [82,83]. This effect of metformin was similarly observed in high fat and fructose diet and diethylnitrosamine-induced hepatocarcinogenesis [84,85]. In a zebrafish model of NAFLD/NASH, metformin treatment was associated with reduced hepatocarcinogenesis, which was attributed to its regulation on the polarization of hepatic macrophages as well as T cell population [86]. In HBV-associated hepatocarcinogenesis, metformin was able to repress the HBX-induced HULC expression, resulting in reduced HCC occurrence and progression [87]. Mechanistically, early intervention of metformin during hepatocarcinogenesis could repress the receptor for advanced glycation end products and inhibit the activation of hepatic progenitor cells [88].
Myoshi et al. found that metformin could induce G0/G1 cell cycle arrest in HCC cells, which was related to the inhibition of G1 cyclins [89], as well as the up-regulation of p21 and p27 [90]. Suppression of HCC cell proliferation by metformin was also attributed to the up-regulation of miR-378, which in turn repressed CDK1 expression and induced G2/M cell cycle arrest [91]. Zhou et al. suggested that metformin-activated AMPK reduced SIRT1 activity, leading to cell senescence instead of apoptosis in HCC xenografts, and resulting in tumor inhibition [92]. The metformin-induced senescence in HCC cells was p53-dependent [53]. Tsai et al. found that metformin activated transcription factor CEBPD via AMPK, which initiated transcription of LC3B and Atg3 and induced autophagy-dependent apoptosis in HCC cells [67]. Apoptosis induced by metformin was dependent to the mitochondrial pathway [93]. Bhat et al. suggested that metformin-induced HCC cell apoptosis and growth inhibition be related to translation inhibition of Mcl-1 oncoprotein and activation of 4E-BPs [94]. Sun et al. suggested that metformin-induced AMPK could stabilize p53, which induced miR-23a to suppress FOXA1 pathway and initiated apoptosis [95]. Metformin-induced AMPK could also decrease Livin expression in HCC and promote cell apoptosis [96]. Metformin also possessed an AMPK-independent anti-proliferative activity against HCC, which could be related to the reduction of oxygen consumption and increased intracellular oxygen tension via down-regulation of HIF-1α [97]. Besides, inhibition of in vivo tumor of HCC by metformin could be associated with the decreased Th1- and Th17-derived IL-22 production through AMPK-dependent STATs down-regulation [98].
Ferritti et al. suggested that metformin suppress the migration and invasion of hepatocellular carcinoma cells dependent on AMPK activation [99]. This effect of metformin was related to its blockade on bFGF-induced Akt/GSK activation, and subsequent Twist1 stabilization [100]. Meanwhile, metformin repressed HCC metastasis through inhibiting tumor angiogenesis. This was related to the inhibition of hepatic stellate cells interaction with vascular endothelial cells in an AMPK-dependent manner [101].
Studies also revealed the potential of metformin as adjuvant therapy. Metformin can suppress the expression of several multidrug resistance proteins, probably through inhibiting NF-κB signaling [102]. Metformin reduced YAP expression and activity and sensitized HCC cells to 5-Fu treatment [103]. Metformin may also potentiate arsenic trioxide toxicity through down-regulation of Bcl-2 in HCC cells [104]. Co-treatment of metformin with regorafenib or sorafenib showed high potency in inhibiting HCC cells, which was associated with the down-regulation of HIF-2α and subsequent up-regulation of TIF30 [105,106,107]. Hsieh et al. showed that AMPK/NF-κB -dependent inhibition of uPA and MMP9 was also involved [108]. Zhang et al. suggested that metformin could block the proliferation and invasion of HCC cells after insufficient radiofrequency ablation. This effect of metformin could be associated with the suppression of Akt survival signaling through AMPK/PTEN [109].

5.2. Berberine

Several lines of evidence have suggested the anti-HCC potential of berberine with multiple mechanisms [110,111,112]. Berberine can induce G0/G1 cell cycle arrest in HCC cells, which was associated with its inhibition on Akt/FoxO3a/Skp2 axis to promote the expression of endogenous CDKi p21 and p27 [113]. The induction of cell apoptosis of HCC by berberine could be AMPK-dependent, which involved mitochondria dysfunction and death receptor five as downstream pathways [64,114]. Induction of autophagic and apoptotic cell death of HCC by berberine was AMPK-dependent, in which ACC acted as the downstream regulator [115]. Hou et al. found that CD147 inhibition was also involved in autophagic and apoptotic cell death induced by berberine [116]. Li et al. showed that arachidonic acid (AA) metabolic pathway was also the target of berberine in inducing HCC cell apoptosis [117]. Another study suggested that AA-associated NF-κB was involved [112]. Berberine could induce expression of miR-21a-3p, which targeted on methionine adenosyltransferase (MAT) to induce apoptosis of HCC cells [118]. Wang et al. showed that another p53-inducible miRNA, miRNA-23a was also involved in berberine’s action in inhibiting HCC by targeting Nek6 [111]. Another miRNA, miR-22, was found to be up-regulated by berberine in HCC, which in turn suppressed cell cycle progression and tumor survival by targeting Cyclin D1 and Bcl-2 [119]. Tsang et al. suggested that Id1 was the principal target of HCC in vivo, in which berberine suppressed Id1 expression to block tumor growth and lung metastasis [120]. The anti-invasive effect of berberine in vitro could be primarily dependent to PAI-1 up-regulation and uPA down-regulation in HCC [121]. Jie et al. showed that berberine treatment could inhibit the VEGF expression in HCC cells, which contributed to the tumor angiogenesis [122]. Furthermore, berberine was found to sensitize HCC cells to chemotherapeutic treatment. Guo et al. suggested that inhibition of CD147 by berberine contributed to the rapamycin sensitivity in HCC cells [123]. Huang et al. showed that berberine could improve sorafenib toxicity to HCC cells by down-regulating the Bcl-2 protein expression [124].

5.3. AICAR

AICAR, a kind of cell-permeable nucleoside, is the antepenultimate metabolic intermediate of the de novo purine synthesis pathway, which was used as the AMPK activator [125]. AICAR was found to repress tumorigenesis in the liver through suppressing IL6/STAT3 activation [126]. In the established HCC, AICAR treatment resulted in HepG2 cell cycle arrest at G1/G1 phase. AICAR inhibited the stem-like cell marker NANOG expression in HepG2 cells via suppressing JNK activity, which suggested the potential of AICAR in inhibiting tumor-initiating cells in HCC [75]. AICAR induced the Nrf2 expression and modulated the cellular redox homeostasis in HCC cells. This effect of AICAR was AMPK-dependent [125]. AICAR activation could significantly inhibit the adhesion of HCC cells onto vascular endothelial cells HUVECs, indicating the ability of AICAR in inhibiting HCC cell migration through blood vessels [74].

5.4. Thienopyridone and Benzimidazole Derivatives

Conventional cytotoxic drugs for HCC like fluorouracil show almost no improvement in survival with severe adverse effects. Sorafenib was successfully found to extend survival of patients with advanced HCC, suggesting a promising strategy of small-molecule targeted chemotherapy [127]. A series of thienopyridone derivatives was synthesized and showed potent activity in killing HCC. The IC50 of these novel compounds was as low as 10 nM [127]. Zhou et al. synthesized a novel thienopyridine derivative compound named TP58. It was found that TP58 could induce G1/S cell cycle arrest in HCC cells with 16 genes being regulated. Further analysis showed that TP58 could regulate some liver-specific transcriptional factors and HCC-specific markers such as HNF-6 and AFP [128]. El-Miligy and colleague synthesized several benzimidazole derivatives, which exhibited dual inhibition on HCV replication and HCC growth, suggesting the prophylactic and curative potential of these compounds on liver cancer [129]. Dai et al. suggested a novel benzimidazole derivative methyl 2-(5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) could induce HCC cells apoptosis without affecting the normal liver cells. MBIC could initiate intracellular reactive species oxygen and activated JNK pathway, which contributed as the main mechanism of MBIC-induced apoptosis. In animals, 25 mg/kg MBIC significantly blocked HCC growth [130].

6. Clinical Perspective of AMPK Activation in HCC Treatment

Given the accumulating pre-clinical evidence showing that AMPK activation could suppress HCC, clinical studies on the efficacy and effectiveness of AMPK activators alone or in combination in treating HCC have been launched. Metformin, as the commonly used anti-diabetics, was generally selected as the pioneer AMPK activator since its well-documented pharmacokinetic and safety profiles. In a recent retrospective study including 5093 patients with HCC, those of whom received metformin treatment showed an improved hepatic function (Child-Pugh-Score A: 69.2% vs. 47.4%; p < 0.001) and underwent more often tumor resection (22.1% vs. 16.5%; p < 0.05) [131]. A nationwide population study in Korea showed that the use of metformin was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events in HCC patients with curative resection [132]. However, the improvement of survival by metformin could not be observed in another study in the United State [133]. metformin showed no beneficial effect in prolonging survival of patients with HCC receiving sorafenib treatment [134]. This might be associated with the increased SIRT3 expression in patients receiving metformin [135]. Another clinical study about patients with advanced HCC revealed worse outcomes with concomitant sorafenib and metformin intervention compared with sorafenib alone, which suggested that the co-treatment of sorafenib and metformin was not helpful in spite of harmless effects [134]. There are several registered on-going clinical trials on the potential use of metformin on HCC.

7. Conclusions

An increasing number of studies have suggested that the intracellular energy sensor signaling AMPK plays an important role in the regulation of human HCC. AMPK signaling was found to be down-regulated in HCC, at kinase activity and expression levels. Down-regulation of AMPK in tumor tissues was associated with the loss of control in tumorigenesis, cell cycle progression, proliferation and survival, invasion and metastasis and cancer metabolism and drug resistance. AMPK activation led to HCC suppression in cell and animal studies. Several AMPK activators, such as metformin, berberine, AICAR, and some thienopyridone/benzimidazole derivatives, were found to be effective in suppressing HCC with their function dependent or independent to AMPK activities, and a few clinical evidence have been gained for the potential repurposing of metformin in HCC treatment. Further translational and clinical investigations are urgently necessary to shed light on the potential of AMPK activators in HCC therapy.

Supplementary Materials

The following are available online at https://www.mdpi.com/2072-6694/11/5/647/s1, Table S1: Regulation of AMPK on HCC.

Author Contributions

Conceptualization, D.W. and N.W.; methodology, validation, formal analysis, investigation, X.J., H.-Y.T.; writing—original draft preparation, X.J., H.-Y.T., D.W. and N.W.; writing—review and editing, S.T., Y.-T.C., D.W. and N.W.; supervision, D.W. and N.W.; funding acquisition, N.W.

Funding

This work is supported by the Health and Medical Fund of Hong Kong S.A.R. (Reference No.: 15162961).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AAArachidonic acid
ACCAcetyl-CoA carboxylase carboxylase
AFPα-fetoprotein
AICAR5-aminoimidazole-4-carboxamide riboside
bFGFBasic fibroblast growth factor
CaMKKCa2+/calmodulin-dependent protein kinase
CDKsCyclin-dependent kinases
CDKIsCDK inhibitors
CEBPDCCAAT/enhancer-binding protein delta
GSPsGrowth suppressor proteins
HCCHepatocellular carcinoma
MATMethionine adenosyltransferase
MBICMethyl 2-(5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate
NAFLDNonalcoholic fatty liver disease
NF-κBNuclear factor kappa-B
PP5Protein phosphatase 5
PPARγPeroxisome proliferator-activated receptor γ
PGC-1αProliferator-activated receptor gamma coactivator 1-alpha
STAT3Signal transducer and activator of transcription 3
TACETranscatheter arterial chemoembolization
TNMTumor–node–metastasis

References

  1. Xie, W.; Qiao, X.; Shang, L.; Dou, J.; Yang, X.; Qiao, S.; Wu, Y. Knockdown of znf233 suppresses hepatocellular carcinoma cell proliferation and tumorigenesis. Gene 2018, 679, 179–185. [Google Scholar] [CrossRef] [PubMed]
  2. Marrero, J.A.; Kulik, L.M.; Sirlin, C.B.; Zhu, A.X.; Finn, R.S.; Abecassis, M.M.; Roberts, L.R.; Heimbach, J.K. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases. Hepatology 2018, 68, 723–750. [Google Scholar] [CrossRef] [PubMed]
  3. McGlynn, K.A.; Petrick, J.L.; London, W.T. Global epidemiology of hepatocellular carcinoma: An emphasis on demographic and regional variability. Clin. Liver Dis. 2015, 19, 223–238. [Google Scholar] [CrossRef]
  4. Li, P.; Huang, W.; Wang, F.; Ke, Y.F.; Gao, L.; Shi, K.Q.; Zhou, M.T.; Chen, B.C. Nomograms based on inflammatory biomarkers for predicting tumor grade and micro-vascular invasion in stage i/ii hepatocellular carcinoma. Biosci. Rep. 2018, 38, 38. [Google Scholar] [CrossRef]
  5. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA: A Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [PubMed]
  6. Han, M.; Gao, H.; Xie, J.; Yuan, Y.P.; Yuan, Q.; Gao, M.Q.; Liu, K.L.; Chen, X.H.; Han, Y.T.; Han, Z.W. Hispidulin induces er stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating ampk signaling pathway. Acta Pharmacol. Sin. 2018, 40, 666–676. [Google Scholar] [CrossRef]
  7. Cheng, Z.; Lei, Z.; Yang, P.; Si, A.; Xiang, D.; Zhou, J.; Huser, N. Long non-coding rna thor promotes cell proliferation and metastasis in hepatocellular carcinoma. Gene 2018, 678, 129–136. [Google Scholar] [CrossRef]
  8. Nies, A.T.; Konig, J.; Pfannschmidt, M.; Klar, E.; Hofmann, W.J.; Keppler, D. Expression of the multidrug resistance proteins mrp2 and mrp3 in human hepatocellular carcinoma. Int. J. Cancer 2001, 94, 492–499. [Google Scholar] [CrossRef]
  9. Murray, G.I.; Paterson, P.J.; Weaver, R.J.; Ewen, S.W.; Melvin, W.T.; Burke, M.D. The expression of cytochrome p-450, epoxide hydrolase, and glutathione s-transferase in hepatocellular carcinoma. Cancer 1993, 71, 36–43. [Google Scholar] [CrossRef]
  10. Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; De Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008, 359, 378–390. [Google Scholar] [CrossRef]
  11. Cheng, A.L.; Kang, Y.K.; Chen, Z.; Tsao, C.J.; Qin, S.; Kim, J.S.; Luo, R.; Feng, J.; Ye, S.; Yang, T.S.; et al. Efficacy and safety of sorafenib in patients in the asia-pacific region with advanced hepatocellular carcinoma: A phase iii randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009, 10, 25–34. [Google Scholar] [CrossRef]
  12. Mihaylova, M.M.; Shaw, R.J. The ampk signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 2011, 13, 1016–1023. [Google Scholar] [CrossRef] [PubMed]
  13. Kahn, B.B.; Alquier, T.; Carling, D.; Hardie, D.G. Amp-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005, 1, 15–25. [Google Scholar] [CrossRef]
  14. Zheng, L.; Yang, W.; Wu, F.; Wang, C.; Yu, L.; Tang, L.; Qiu, B.; Li, Y.; Guo, L.; Wu, M.; et al. Prognostic significance of ampk activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin. Cancer Res. 2013, 19, 5372–5380. [Google Scholar] [CrossRef] [PubMed]
  15. Hardie, D.G. Ampk: A key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. 2008, 32 (Suppl. 4), S7–S12. [Google Scholar] [CrossRef]
  16. Ruderman, N.B.; Carling, D.; Prentki, M.; Cacicedo, J.M. Ampk, insulin resistance, and the metabolic syndrome. J. Clin. Investig. 2013, 123, 2764–2772. [Google Scholar] [CrossRef] [PubMed]
  17. Cordero, M.D.; Williams, M.R.; Ryffel, B. Amp-activated protein kinase regulation of the nlrp3 inflammasome during aging. Trends Endocrinol. Metab. 2018, 29, 8–17. [Google Scholar] [CrossRef]
  18. Tain, Y.L.; Hsu, C.N. Amp-activated protein kinase as a reprogramming strategy for hypertension and kidney disease of developmental origin. Int. J. Mol. Sci. 2018, 19, 1744. [Google Scholar] [CrossRef] [PubMed]
  19. Li, X.; Liu, J.; Lu, Q.; Ren, D.; Sun, X.; Rousselle, T.; Tan, Y.; Li, J. Ampk: A therapeutic target of heart failure-not only metabolism regulation. Biosci. Rep. 2019, 39. [Google Scholar] [CrossRef]
  20. Smith, B.K.; Marcinko, K.; Desjardins, E.M.; Lally, J.S.; Ford, R.J.; Steinberg, G.R. Treatment of nonalcoholic fatty liver disease: Role of ampk. Am. J. Physiol.-Endocrinol. Metab. 2016, 311, E730–E740. [Google Scholar] [CrossRef] [PubMed]
  21. Umezawa, S.; Higurashi, T.; Nakajima, A. Ampk: Therapeutic target for diabetes and cancer prevention. Curr. Pharm. Des. 2017, 23, 3629–3644. [Google Scholar] [CrossRef] [PubMed]
  22. Cao, W.; Li, J.; Hao, Q.; Vadgama, J.V.; Wu, Y. Amp-activated protein kinase: A potential therapeutic target for triple-negative breast cancer. Breast Cancer Res. 2019, 21, 29. [Google Scholar] [CrossRef]
  23. Kim, A.S.; Miller, E.J.; Young, L.H. Amp-activated protein kinase: A core signalling pathway in the heart. Acta Physiol. (Oxf.) 2009, 196, 37–53. [Google Scholar] [CrossRef] [PubMed]
  24. Viollet, B.; Andreelli, F.; Jorgensen, S.B.; Perrin, C.; Flamez, D.; Mu, J.; Wojtaszewski, J.F.P.; Schuit, F.C.; Birnbaum, M.; Richter, E.; et al. Physiological role of amp-activated protein kinase (ampk): Insights from knockout mouse models. Biochem. Soc. Trans. 2003, 31, 216–219. [Google Scholar] [CrossRef] [PubMed]
  25. Bairwa, S.C.; Parajuli, N.; Dyck, J.R. The role of ampk in cardiomyocyte health and survival. Biochimica et Biophysica Acta 2016, 1862, 2199–2210. [Google Scholar] [CrossRef] [PubMed]
  26. Zaha, V.G.; Young, L.H. Amp-activated protein kinase regulation and biological actions in the heart. Circ. Res. 2012, 111, 800–814. [Google Scholar] [CrossRef] [PubMed]
  27. Hardie, D.G.; Carling, D.; Gamblin, S.J. Amp-activated protein kinase: Also regulated by adp? Trends Biochem. Sci. 2011, 36, 470–477. [Google Scholar] [CrossRef] [PubMed]
  28. Sanz, P.; Rubio, T.; Garcia-Gimeno, M.A. Ampkbeta subunits: More than just a scaffold in the formation of ampk complex. FEBS J. 2013, 280, 3723–3733. [Google Scholar] [CrossRef]
  29. Fogarty, S.; Hardie, D.G. Development of protein kinase activators: Ampk as a target in metabolic disorders and cancer. Biochimica et Biophysica Acta 2010, 1804, 581–591. [Google Scholar] [CrossRef]
  30. Davies, S.P.; Helps, N.R.; Cohen, P.T.; Hardie, D.G. 5’-amp inhibits dephosphorylation, as well as promoting phosphorylation, of the amp-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2c alpha and native bovine protein phosphatase-2ac. FEBS Lett. 1995, 377, 421–425. [Google Scholar]
  31. Marin, T.L.; Gongol, B.; Zhang, F.; Martin, M.; Johnson, D.A.; Xiao, H.; Wang, Y.; Subramaniam, S.; Chien, S.; Shyy, J.Y.J. Ampk promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors dnmt1, rbbp7, and hat1. Sci. Signal. 2017, 10, eaaf7478. [Google Scholar] [CrossRef]
  32. Lee, S.R.; Kwon, S.W.; Lee, Y.H.; Kaya, P.; Kim, J.M.; Ahn, C.; Jung, E.M.; Lee, G.S.; An, B.S.; Jeung, E.B.; et al. Dietary intake of genistein suppresses hepatocellular carcinoma through ampk-mediated apoptosis and anti-inflammation. BMC Cancer 2019, 19, 12. [Google Scholar] [CrossRef]
  33. Wang, L.; Li, H.; Zhen, Z.; Ma, X.; Yu, W.; Zeng, H.; Li, L. Cxcl17 promotes cell metastasis and inhibits autophagy via the lkb1-ampk pathway in hepatocellular carcinoma. Gene 2019, 690, 129–136. [Google Scholar] [CrossRef]
  34. Yang, X.; Liu, Y.; Li, M.; Wu, H.; Wang, Y.; You, Y.; Li, P.; Ding, X.; Liu, C.; Gong, J. Predictive and preventive significance of ampk activation on hepatocarcinogenesis in patients with liver cirrhosis. Cell Death Dis. 2018, 9, 264. [Google Scholar] [CrossRef]
  35. Zheng, L.Y.; Wu, L.; Lu, J.; Zou, D.J.; Huang, Q. Expression of phosphorylated amp-activated protein kinase predicts response to transarterial chemoembolization in postoperative cases of hepatocellular carcinoma. Medicine 2016, 95, e2908. [Google Scholar] [CrossRef]
  36. Cai, C.; Wang, W.; Tu, Z. Aberrantly DNA methylated-differentially expressed genes and pathways in hepatocellular carcinoma. J. Cancer 2019, 10, 355–366. [Google Scholar] [CrossRef]
  37. Huang; Li, T.; Wang, L.; Zhang, L.; Yan, R.; Li, K.; Xing, S.; Wu, G.; Hu, L.; Jia, W.; et al. Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress. Cell Res. 2016, 26, 1112–1130. [Google Scholar] [CrossRef] [Green Version]
  38. Zhang, Z.Y.; Hong, D.; Nam, S.H.; Kim, J.M.; Paik, Y.H.; Joh, J.W.; Kwon, C.H.; Park, J.B.; Choi, G.S.; Jang, K.Y.; et al. Sirt1 regulates oncogenesis via a mutant p53-dependent pathway in hepatocellular carcinoma. J. Hepatol. 2015, 62, 121–130. [Google Scholar] [CrossRef]
  39. Chen, Y.L.; Hung, M.H.; Chu, P.Y.; Chao, T.I.; Tsai, M.H.; Chen, L.J.; Hsiao, Y.J.; Shih, C.T.; Hsieh, F.S.; Chen, K.F. Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with amp-activated protein kinase. Biochem. Pharmacol. 2017, 138, 49–60. [Google Scholar] [CrossRef]
  40. Hsieh, F.S.; Chen, Y.L.; Hung, M.H.; Chu, P.Y.; Tsai, M.H.; Chen, L.J.; Hsiao, Y.J.; Shih, C.T.; Chang, M.J.; Chao, T.I.; et al. Palbociclib induces activation of ampk and inhibits hepatocellular carcinoma in a cdk4/6-independent manner. Mol. Oncol. 2017, 11, 1035–1049. [Google Scholar] [CrossRef]
  41. Cheng, J.; Huang, T.; Li, Y.; Guo, Y.; Zhu, Y.; Wang, Q.; Tan, X.; Chen, W.; Zhang, Y.; Cheng, W.; et al. Amp-activated protein kinase suppresses the in vitro and in vivo proliferation of hepatocellular carcinoma. PLoS ONE 2014, 9, e93256. [Google Scholar] [CrossRef] [PubMed]
  42. Grana, X.; Reddy, E.P. Cell cycle control in mammalian cells: Role of cyclins, cyclin dependent kinases (cdks), growth suppressor genes and cyclin-dependent kinase inhibitors (ckis). Oncogene 1995, 11, 211–219. [Google Scholar] [PubMed]
  43. Tuo, L.; Xiang, J.; Pan, X.; Hu, J.; Tang, H.; Liang, L.; Xia, J.; Hu, Y.; Zhang, W.; Huang, A.; et al. Pck1 negatively regulates cell cycle progression and hepatoma cell proliferation via the ampk/p27(kip1) axis. J. Exp. Clin. Cancer Res. 2019, 38, 50. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, S.T.; Ho, H.J.; Lin, J.T.; Shieh, J.J.; Wu, C.Y. Simvastatin-induced cell cycle arrest through inhibition of stat3/skp2 axis and activation of ampk to promote p27 and p21 accumulation in hepatocellular carcinoma cells. Cell Death Dis. 2017, 8, e2626. [Google Scholar] [CrossRef] [PubMed]
  45. Zheng, Y.S.; Zhang, J.Y.; Zhang, D.H. Fatsioside ainduced apoptotic death of hepg2 cells requires activation of ampactivated protein kinase. Mol. Med. Rep. 2015, 12, 5679–5684. [Google Scholar] [CrossRef] [PubMed]
  46. Kawaguchi, T.; Hayakawa, M.; Koga, H.; Torimura, T. Effects of fucoidan on proliferation, amp-activated protein kinase, and downstream metabolism- and cell cycle-associated molecules in poorly differentiated human hepatoma hlf cells. Int. J. Oncol. 2015, 46, 2216–2222. [Google Scholar] [CrossRef]
  47. Wang, Q.; Wang, Y.; Xing, Y.; Yan, Y.; Guo, P.; Zhuang, J.; Qin, F.; Zhang, J. Physcion 8-o-beta-glucopyranoside induces apoptosis, suppresses invasion and inhibits epithelial to mesenchymal transition of hepatocellular carcinoma hepg2 cells. Biomed. Pharmacother. 2016, 83, 372–380. [Google Scholar] [CrossRef] [PubMed]
  48. Pan, X.; Wang, H.; Tong, D.; Wang, C.; Sun, L.; Zhao, C.; Li, Y.; Zhu, L.; Wu, D. Physcion induces apoptosis in hepatocellular carcinoma by modulating mir-370. Am. J. Cancer Res. 2016, 6, 2919–2931. [Google Scholar] [PubMed]
  49. Yie, Y.; Zhao, S.; Tang, Q.; Zheng, F.; Wu, J.; Yang, L.; Deng, S.; Hann, S.S. Ursolic acid inhibited growth of hepatocellular carcinoma hepg2 cells through ampkalpha-mediated reduction of DNA methyltransferase 1. Mol. Cell. Biochem. 2015, 402, 63–74. [Google Scholar] [CrossRef]
  50. Stein, U.; Arlt, F.; Walther, W.; Smith, J.; Waldman, T.; Harris, E.D.; Mertins, S.D.; Heizmann, C.W.; Allard, D.; Birchmeier, W.; et al. The metastasis-associated gene s100a4 is a novel target of beta-catenin/t-cell factor signaling in colon cancer. Gastroenterology 2006, 131, 1486–1500. [Google Scholar] [CrossRef]
  51. Park, S.Y.; Lee, Y.K.; Kim, H.J.; Park, O.J.; Kim, Y.M. Ampk interacts with beta-catenin in the regulation of hepatocellular carcinoma cell proliferation and survival with selenium treatment. Oncol. Rep. 2016, 35, 1566–1572. [Google Scholar] [CrossRef] [PubMed]
  52. Chiang, P.C.; Lin, S.C.; Pan, S.L.; Kuo, C.H.; Tsai, I.L.; Kuo, M.T.; Wen, W.C.; Chen, P.; Guh, J.H. Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells: A crucial role of ampk and mtor pathways. Biochem. Pharmacol. 2010, 79, 162–171. [Google Scholar] [CrossRef] [PubMed]
  53. Yi, G.; He, Z.; Zhou, X.; Xian, L.; Yuan, T.; Jia, X.; Hong, J.; He, L.; Liu, J. Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the ampk pathway. Int. J. Oncol. 2013, 43, 1503–1510. [Google Scholar] [CrossRef]
  54. Sun, X.L.; Gao, L.; Chien, H.Y.; Li, W.C.; Zhao, J.J. The regulation and function of the nuak family. J. Mol. Endocrinol. 2013, 51, R15–R22. [Google Scholar] [CrossRef] [PubMed]
  55. Yuan, W.C.; Pepe-Mooney, B.; Galli, G.G.; Dill, M.T.; Huang, H.T.; Hao, M.F.; Wang, Y.M.; Liang, H.; Calogero, R.A.; Camargo, F.D. Nuak2 is a critical yap target in liver cancer. Nat. Commun. 2018, 9, 12. [Google Scholar] [CrossRef]
  56. Goto, K.; Lin, W.Y.; Zhang, L.L.; Jilg, N.; Shao, R.X.; Schaefer, E.A.K.; Zhao, H.; Fusco, D.N.; Peng, L.F.; Kato, N.; et al. The ampk-related kinase snark regulates hepatitis c virus replication and pathogenesis through enhancement of tgf-beta signaling. J. Hepatol. 2013, 59, 942–948. [Google Scholar] [CrossRef]
  57. Goto, K.; Kato, N.; Chung, R.T. Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the ampk-related kinase snark in vitro. Oncotarget 2016, 7, 74987–74999. [Google Scholar] [CrossRef]
  58. Martinez-Lopez, N.; Garcia-Rodriguez, J.L.; Varela-Rey, M.; Gutierrez, V.; Fernandez-Ramos, D.; Beraza, N.; Aransay, A.M.; Schlangen, K.; Lozano, J.J.; Aspichueta, P.; et al. Hepatoma cells from mice deficient in glycine n-methyltransferase have increased ras signaling and activation of liver kinase b1. Gastroenterology 2012, 143, 787–798e713. [Google Scholar] [CrossRef]
  59. Liu, X.; Hu, X.; Kuang, Y.; Yan, P.; Li, L.; Li, C.; Tao, Q.; Cai, X. Bclb, methylated in hepatocellular carcinoma, is a starvation stress sensor that induces apoptosis and autophagy through the ampk-mtor signaling cascade. Cancer Lett. 2017, 395, 63–71. [Google Scholar] [CrossRef]
  60. Zhang, X.; Han, K.; Yuan, D.H.; Meng, C.Y. Overexpression of nad(p)h: Quinone oxidoreductase 1 inhibits hepatocellular carcinoma cell proliferation and induced apoptosis by activating ampk/pgc-1alpha pathway. DNA Cell Biol. 2017, 36, 256–263. [Google Scholar] [CrossRef]
  61. Han, M.; Gao, H.; Ju, P.; Gao, M.Q.; Yuan, Y.P.; Chen, X.H.; Liu, K.L.; Han, Y.T.; Han, Z.W. Hispidulin inhibits hepatocellular carcinoma growth and metastasis through ampk and erk signaling mediated activation of ppargamma. Biomed. Pharmacother. 2018, 103, 272–283. [Google Scholar] [CrossRef]
  62. Kim, Y.W.; Jang, E.J.; Kim, C.H.; Lee, J.H. Sauchinone exerts anticancer effects by targeting ampk signaling in hepatocellular carcinoma cells. Chem.-Biol. Interact. 2017, 261, 108–117. [Google Scholar] [CrossRef]
  63. Pan, X.P.; Wang, C.; Li, Y.; Huang, L.H. Physcion induces apoptosis through triggering endoplasmic reticulum stress in hepatocellular carcinoma. Biomed. Pharmacother. 2018, 99, 894–903. [Google Scholar] [CrossRef]
  64. Yang, X.; Huang, N. Berberine induces selective apoptosis through the ampkmediated mitochondrial/caspase pathway in hepatocellular carcinoma. Mol. Med. Rep. 2013, 8, 505–510. [Google Scholar] [CrossRef]
  65. Lee, C.W.; Wong, L.L.; Tse, E.Y.; Liu, H.F.; Leong, V.Y.; Lee, J.M.; Hardie, D.G.; Ng, I.O.; Ching, Y.P. Ampk promotes p53 acetylation via phosphorylation and inactivation of sirt1 in liver cancer cells. Cancer Res. 2012, 72, 4394–4404. [Google Scholar] [CrossRef] [PubMed]
  66. Li, L.; Hong, H.H.; Chen, S.P.; Ma, C.Q.; Liu, H.Y.; Yao, Y.C. Activation of ampk/mnsod signaling mediates anti-apoptotic effect of hepatitis b virus in hepatoma cells. World J. Gastroenterol. 2016, 22, 4345–4353. [Google Scholar] [CrossRef] [PubMed]
  67. Tsai, H.H.; Lai, H.Y.; Chen, Y.C.; Li, C.F.; Huang, H.S.; Liu, H.S.; Tsai, Y.S.; Wang, J.M. Metformin promotes apoptosis in hepatocellular carcinoma through the cebpd-induced autophagy pathway. Oncotarget 2017, 8, 13832–13845. [Google Scholar] [CrossRef]
  68. Zhong, J.; Dong, X.; Xiu, P.; Wang, F.; Liu, J.; Wei, H.; Xu, Z.; Liu, F.; Li, T.; Li, J. Blocking autophagy enhances meloxicam lethality to hepatocellular carcinoma by promotion of endoplasmic reticulum stress. Cell Prolif. 2015, 48, 691–704. [Google Scholar] [CrossRef] [PubMed]
  69. Huang, G.M.; Jiang, Q.H.; Cai, C.; Qu, M.; Shen, W. Scd1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the ampk signaling pathway. Cancer Lett. 2015, 358, 180–190. [Google Scholar] [CrossRef] [PubMed]
  70. Wang, N.; Feng, Y.; Zhu, M.; Siu, F.M.; Ng, K.M.; Che, C.M. A novel mechanism of xiap degradation induced by timosaponin aiii in hepatocellular carcinoma. Biochim. Biophys. Acta 2013, 1833, 2890–2899. [Google Scholar] [CrossRef] [PubMed]
  71. Ma, M.; Xu, H.; Liu, G.; Wu, J.; Li, C.; Wang, X.; Zhang, S.; Xu, H.; Ju, S.; Cheng, W.; et al. Mita1, a novel energy stress-inducible lncrna, promotes hepatocellular carcinoma metastasis. Hepatology 2019. [Google Scholar] [CrossRef]
  72. Li, M.; Jin, C.; Xu, M.; Zhou, L.; Li, D.; Yin, Y. Bifunctional enzyme atic promotes propagation of hepatocellular carcinoma by regulating ampk-mtor-s6 k1 signaling. Cell Commun. Signal. 2017, 15, 52. [Google Scholar] [CrossRef]
  73. Chen, Y.; Zhao, Z.X.; Huang, F.; Yuan, X.W.; Deng, L.; Tang, D. Microrna-1271 functions as a potential tumor suppressor in hepatitis b virus-associated hepatocellular carcinoma through the ampk signaling pathway by binding to ccna1. J. Cell. Physiol. 2019, 234, 3555–3569. [Google Scholar] [CrossRef]
  74. Yang, C.C.; Chang, S.F.; Chao, J.K.; Lai, Y.L.; Chang, W.E.; Hsu, W.H.; Kuo, W.H. Activation of amp-activated protein kinase attenuates hepatocellular carcinoma cell adhesion stimulated by adipokine resistin. BMC Cancer 2014, 14, 112. [Google Scholar] [CrossRef]
  75. Shen, C.; Ka, S.O.; Kim, S.J.; Kim, J.H.; Park, B.H.; Park, J.H. Metformin and aicar regulate nanog expression via the jnk pathway in hepg2 cells independently of ampk. Tumour Biol. 2016, 37, 11199–11208. [Google Scholar] [CrossRef]
  76. Pascale, R.M.; Feo, C.F.; Calvisi, D.F.; Feo, F. Deregulation of methionine metabolism as determinant of progression and prognosis of hepatocellular carcinoma. Transl. Gastroenterol. Hepatol. 2018, 3, 36. [Google Scholar] [CrossRef] [PubMed]
  77. Kim, G.Y.; Kwon, J.H.; Cho, J.H.; Zhang, L.; Mansfield, B.C.; Chou, J.Y. Downregulation of pathways implicated in liver inflammation and tumorigenesis of glycogen storage disease type ia mice receiving gene therapy. Hum. Mol. Genet. 2017, 26, 1890–1899. [Google Scholar] [CrossRef]
  78. Lally, J.S.V.; Ghoshal, S.; DePeralta, D.K.; Moaven, O.; Wei, L.; Masia, R.; Erstad, D.J.; Fujiwara, N.; Leong, V.; Houde, V.P.; et al. Inhibition of acetyl-coa carboxylase by phosphorylation or the inhibitor nd-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. 2019, 29, 174–182e175. [Google Scholar] [CrossRef] [PubMed]
  79. Wang, N.; Feng, Y.; Tan, H.Y.; Cheung, F.; Hong, M.; Lao, L.; Nagamatsu, T. Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation huanglian-jiedu decoction in human hepatocellular carcinoma. J. Ethnopharmacol. 2015, 164, 309–318. [Google Scholar] [CrossRef]
  80. Bagga, S.; Rawat, S.; Ajenjo, M.; Bouchard, M.J. Hepatitis b virus (hbv) x protein-mediated regulation of hepatocyte metabolic pathways affects viral replication. Virology 2016, 498, 9–22. [Google Scholar] [CrossRef] [PubMed]
  81. Kim, J.; Yang, G.; Kim, Y.; Kim, J.; Ha, J. Ampk activators: Mechanisms of action and physiological activities. Exp. Mol. Med. 2016, 48, e224. [Google Scholar] [CrossRef] [PubMed]
  82. Zhang, C.; Hu, J.J.; Sheng, L.; Yuan, M.; Wu, Y.; Chen, L.; Zheng, G.H.; Qiu, Z.P. Metformin delays akt/c-met-driven hepatocarcinogenesis by regulating signaling pathways for de novo lipogenesis and atp generation. Toxicol. Appl. Pharmacol. 2019, 365, 51–60. [Google Scholar] [CrossRef] [PubMed]
  83. Bhalla, K.; Hwang, B.J.; Dewi, R.E.; Twaddel, W.; Goloubeva, O.G.; Wong, K.K.; Saxena, N.K.; Biswal, S.; Girnun, G.D. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev. Res. 2012, 5, 544–552. [Google Scholar] [CrossRef] [Green Version]
  84. Cauchy, F.; Mebarki, M.; Leporq, B.; Laouirem, S.; Albuquerque, M.; Lambert, S.; Bourgoin, P.; Soubrane, O.; Van Beers, B.E.; Faivre, S.; et al. Strong antineoplastic effects of metformin in preclinical models of liver carcinogenesis. Clin. Sci. 2017, 131, 27–36. [Google Scholar] [CrossRef]
  85. Jo, W.; Yu, E.S.; Chang, M.; Park, H.K.; Choi, H.J.; Ryu, J.E.; Jang, S.; Lee, H.J.; Jang, J.J.; Son, W.C. Metformin inhibits early stage diethylnitrosamineinduced hepatocarcinogenesis in rats. Mol. Med. Rep. 2016, 13, 146–152. [Google Scholar] [CrossRef]
  86. De Oliveira, S.; Houseright, R.A.; Graves, A.L.; Golenberg, N.; Korte, B.G.; Miskolci, V.; Huttenlocher, A. Metformin modulates innate immune-mediated inflammation and early progression of nafld-associated hepatocellular carcinoma in zebrafish. J. Hepatol. 2019, 70, 710–721. [Google Scholar] [CrossRef]
  87. Jiang, Z.; Liu, H. Metformin inhibits tumorigenesis in hbv-induced hepatocellular carcinoma by suppressing hulc overexpression caused by hbx. J. Cell. Biochem. 2018, 119, 4482–4495. [Google Scholar] [CrossRef] [PubMed]
  88. DePeralta, D.K.; Wei, L.; Ghoshal, S.; Schmidt, B.; Lauwers, G.Y.; Lanuti, M.; Chung, R.T.; Tanabe, K.K.; Fuchs, B.C. Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis. Cancer 2016, 122, 1216–1227. [Google Scholar] [CrossRef] [PubMed]
  89. Miyoshi, H.; Kato, K.; Iwama, H.; Maeda, E.; Sakamoto, T.; Fujita, K.; Toyota, Y.; Tani, J.; Nomura, T.; Mimura, S.; et al. Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo. Int. J. Oncol. 2014, 45, 322–332. [Google Scholar] [CrossRef]
  90. Cai, X.; Hu, X.; Cai, B.; Wang, Q.; Li, Y.; Tan, X.; Hu, H.; Chen, X.; Huang, J.; Cheng, J.; et al. Metformin suppresses hepatocellular carcinoma cell growth through induction of cell cycle g1/g0 phase arrest and p21cip and p27kip expression and downregulation of cyclin d1 in vitro and in vivo. Oncol. Rep. 2013, 30, 2449–2457. [Google Scholar] [CrossRef] [PubMed]
  91. Zhou, J.; Han, S.; Qian, W.; Gu, Y.; Li, X.; Yang, K. Metformin induces mir-378 to downregulate the cdk1, leading to suppression of cell proliferation in hepatocellular carcinoma. Onco Targets Ther. 2018, 11, 4451–4459. [Google Scholar] [CrossRef]
  92. Zhou, X.; Chen, J.; Chen, L.; Feng, X.; Liu, Z.; Hu; Zeng, Z.; Jia, X.; Liang, M.; Shi, B.; et al. Negative regulation of sirtuin 1 by amp-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts. Cancer Lett. 2017, 411, 1–11. [Google Scholar] [CrossRef] [PubMed]
  93. Xiong, Y.; Lu, Q.J.; Zhao, J.; Wu, G.Y. Metformin inhibits growth of hepatocellular carcinoma cells by inducing apoptosis via mitochondrion-mediated pathway. Asian Pac. J. Cancer Prev. 2012, 13, 3275–3279. [Google Scholar] [CrossRef] [PubMed]
  94. Bhat, M.; Yanagiya, A.; Graber, T.; Razumilava, N.; Bronk, S.; Zammit, D.; Zhao, Y.; Zakaria, C.; Metrakos, P.; Pollak, M.; et al. Metformin requires 4e-bps to induce apoptosis and repress translation of mcl-1 in hepatocellular carcinoma cells. Oncotarget 2017, 8, 50542–50556. [Google Scholar] [CrossRef] [PubMed]
  95. Sun, Y.; Tao, C.; Huang, X.; He, H.; Shi, H.; Zhang, Q.; Wu, H. Metformin induces apoptosis of human hepatocellular carcinoma hepg2 cells by activating an ampk/p53/mir-23a/foxa1 pathway. Onco Targets Ther. 2016, 9, 2845–2853. [Google Scholar] [PubMed]
  96. Qu, Z.; Zhang, Y.; Liao, M.; Chen, Y.; Zhao, J.; Pan, Y. In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma. Hepatol. Res. 2012, 42, 922–933. [Google Scholar] [CrossRef] [PubMed]
  97. Zhou, X.; Chen, J.; Yi, G.; Deng, M.; Liu, H.; Liang, M.; Shi, B.; Fu, X.; Chen, Y.; Chen, L.; et al. Metformin suppresses hypoxia-induced stabilization of hif-1alpha through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget 2016, 7, 873–884. [Google Scholar] [PubMed]
  98. Zhao, D.; Long, X.D.; Lu, T.F.; Wang, T.; Zhang, W.W.; Liu, Y.X.; Cui, X.L.; Dai, H.J.; Xue, F.; Xia, Q. Metformin decreases il-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma. Int. J. Cancer 2015, 136, 2556–2565. [Google Scholar] [CrossRef]
  99. Ferretti, A.C.; Hidalgo, F.; Tonucci, F.M.; Almada, E.; Pariani, A.; Larocca, M.C.; Favre, C. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: Targeting ampk activation to control migration. Sci. Rep. 2019, 9, 2815. [Google Scholar] [CrossRef]
  100. Chengye, W.; Yu, T.; Ping, S.; Deguang, S.; Keyun, W.; Yan, W.; Rixin, Z.; Rui, L.; Zhenming, G.; Mingliang, Y.; et al. Metformin reverses bfgf-induced epithelial-mesenchymal transition in hcc cells. Oncotarget 2017, 8, 104247–104257. [Google Scholar] [CrossRef]
  101. Qu, H.; Yang, X. Metformin inhibits angiogenesis induced by interaction of hepatocellular carcinoma with hepatic stellate cells. Cell Biochem. Biophys. 2015, 71, 931–936. [Google Scholar] [CrossRef]
  102. Wu, W.; Yang, J.L.; Wang, Y.L.; Wang, H.; Yao, M.; Wang, L.; Gu, J.J.; Cai, Y.; Shi, Y.; Yao, D.F. Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibiting nf-kappab gene transcription. World J. Hepatol. 2016, 8, 985–993. [Google Scholar] [CrossRef]
  103. Tian, Y.; Tang, B.; Wang, C.; Sun, D.; Zhang, R.; Luo, N.; Han, Z.; Liang, R.; Gao, Z.; Wang, L. Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of yap. Oncotarget 2016, 7, 46230–46241. [Google Scholar] [CrossRef] [PubMed]
  104. Yang, X.; Sun, D.; Tian, Y.; Ling, S.; Wang, L. Metformin sensitizes hepatocellular carcinoma to arsenic trioxide-induced apoptosis by downregulating bcl2 expression. Tumour Biol. 2015, 36, 2957–2964. [Google Scholar] [CrossRef] [PubMed]
  105. Yang, Q.; Guo, X.; Yang, L. Metformin enhances the effect of regorafenib and inhibits recurrence and metastasis of hepatic carcinoma after liver resection via regulating expression of hypoxia inducible factors 2alpha (hif-2alpha) and 30 kda hiv tat-interacting protein (tip30). Med. Sci. Monit. 2018, 24, 2225–2234. [Google Scholar] [CrossRef] [PubMed]
  106. Guo, Z.; Cao, M.; You, A.; Gao, J.; Zhou, H.; Li, H.; Cui, Y.; Fang, F.; Zhang, W.; Song, T.; et al. Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of tip30. Cancer Sci. 2016, 107, 507–513. [Google Scholar] [CrossRef]
  107. You, A.; Cao, M.; Guo, Z.; Zuo, B.; Gao, J.; Zhou, H.; Li, H.; Cui, Y.; Fang, F.; Zhang, W.; et al. Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models. J. Hematol. Oncol. 2016, 9, 20. [Google Scholar] [CrossRef] [Green Version]
  108. Hsieh, S.C.; Tsai, J.P.; Yang, S.F.; Tang, M.J.; Hsieh, Y.H. Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the erk/jnk-mediated nf-kappab-dependent pathway that reduces upa and mmp-9 expression. Amino Acids 2014, 46, 2809–2822. [Google Scholar] [CrossRef]
  109. Zhang, Q.; Kong, J.; Dong, S.; Xu, W.; Sun, W. Metformin exhibits the anti-proliferation and anti-invasion effects in hepatocellular carcinoma cells after insufficient radiofrequency ablation. Cancer Cell Int. 2017, 17, 48. [Google Scholar] [CrossRef] [Green Version]
  110. Chuang, T.Y.; Wu, H.L.; Min, J.; Diamond, M.; Azziz, R.; Chen, Y.H. Berberine regulates the protein expression of multiple tumorigenesis-related genes in hepatocellular carcinoma cell lines. Cancer Cell Int. 2017, 17, 59. [Google Scholar] [CrossRef] [Green Version]
  111. Wang, N.; Zhu, M.F.; Wang, X.B.; Tan, H.Y.; Tsao, S.W.; Feng, Y.B. Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of mir-23a in hepatocellular carcinoma. Biochim. Biophys. Acta-Gene Regul. Mech. 2014, 1839, 849–857. [Google Scholar] [CrossRef] [PubMed]
  112. Li, M.; Zhang, M.; Zhang, Z.L.; Liu, N.; Han, X.Y.; Liu, Q.C.; Deng, W.J.; Liao, C.X. Induction of apoptosis by berberine in hepatocellular carcinoma hepg2 cells via downregulation of nf-kappa b. Oncol. Res. 2017, 25, 233–239. [Google Scholar] [CrossRef] [PubMed]
  113. Li, F.; Dong, X.; Lin, P.; Jiang, J. Regulation of akt/foxo3a/skp2 axis is critically involved in berberine-induced cell cycle arrest in hepatocellular carcinoma cells. Int. J. Mol. Sci. 2018, 19, 327. [Google Scholar]
  114. Ke, R.; Vishnoi, K.; Viswakarma, N.; Santha, S.; Das, S.; Rana, A.; Rana, B. Involvement of amp-activated protein kinase and death receptor 5 in trail-berberine-induced apoptosis of cancer cells. Sci. Rep. 2018, 8, 5521. [Google Scholar] [CrossRef] [PubMed]
  115. Yu, R.; Zhang, Z.Q.; Wang, B.; Jiang, H.X.; Cheng, L.; Shen, L.M. Berberine-induced apoptotic and autophagic death of hepg2 cells requires ampk activation. Cancer Cell Int. 2014, 14, 49. [Google Scholar] [CrossRef] [PubMed]
  116. Hou, Q.; Tang, X.; Liu, H.; Tang, J.; Yang, Y.; Jing, X.; Xiao, Q.; Wang, W.; Gou, X.; Wang, Z. Berberine induces cell death in human hepatoma cells in vitro by downregulating cd147. Cancer Sci. 2011, 102, 1287–1292. [Google Scholar] [CrossRef]
  117. Li, J.; Li, O.; Kan, M.; Zhang, M.; Shao, D.; Pan, Y.; Zheng, H.; Zhang, X.; Chen, L.; Liu, S. Berberine induces apoptosis by suppressing the arachidonic acid metabolic pathway in hepatocellular carcinoma. Mol. Med. Rep. 2015, 12, 4572–4577. [Google Scholar] [CrossRef]
  118. Lo, T.F.; Tsai, W.C.; Chen, S.T. Microrna-21-3p, a berberine-induced mirna, directly down-regulates human methionine adenosyltransferases 2a and 2b and inhibits hepatoma cell growth. PLoS ONE 2013, 8, e75628. [Google Scholar] [CrossRef]
  119. Chen, J.; Wu, F.X.; Luo, H.L.; Liu, J.J.; Luo, T.; Bai, T.; Li, L.Q.; Fan, X.H. Berberine upregulates mir-22-3p to suppress hepatocellular carcinoma cell proliferation by targeting sp1. Am. J. Transl. Res. 2016, 8, 4932–4941. [Google Scholar]
  120. Tsang, C.M.; Cheung, K.C.; Cheung, Y.C.; Man, K.; Lui, V.W.; Tsao, S.W.; Feng, Y. Berberine suppresses id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochimica et Biophysica Acta 2015, 1852, 541–551. [Google Scholar] [CrossRef]
  121. Wang, X.; Wang, N.; Li, H.; Liu, M.; Cao, F.; Yu, X.; Zhang, J.; Tan, Y.; Xiang, L.; Feng, Y. Up-regulation of pai-1 and down-regulation of upa are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine. Int. J. Mol. Sci. 2016, 17, 577. [Google Scholar] [CrossRef] [PubMed]
  122. Jie, S.; Li, H.; Tian, Y.; Guo, D.; Zhu, J.; Gao, S.; Jiang, L. Berberine inhibits angiogenic potential of hep g2 cell line through vegf down-regulation in vitro. J. Gastroenterol. Hepatol. 2011, 26, 179–185. [Google Scholar] [CrossRef]
  123. Guo, N.; Yan, A.; Gao, X.; Chen, Y.; He, X.; Hu, Z.; Mi, M.; Tang, X.; Gou, X. Berberine sensitizes rapamycinmediated human hepatoma cell death in vitro. Mol. Med. Rep. 2014, 10, 3132–3138. [Google Scholar] [CrossRef]
  124. Huang, Y.; Wang, K.; Gu, C.; Yu, G.; Zhao, D.; Mai, W.; Zhong, Y.; Liu, S.; Nie, Y.; Yang, H. Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib. Oncol. Rep. 2018, 40, 1525–1532. [Google Scholar] [CrossRef]
  125. Sid, B.; Glorieux, C.; Valenzuela, M.; Rommelaere, G.; Najimi, M.; Dejeans, N.; Renard, P.; Verrax, J.; Calderon, P.B. Aicar induces nrf2 activation by an ampk-independent mechanism in hepatocarcinoma cells. Biochem. Pharmacol. 2014, 91, 168–180. [Google Scholar] [CrossRef]
  126. Gao, J.; Xiong, R.; Xiong, D.; Zhao, W.; Zhang, S.; Yin, T.; Zhang, X.; Jiang, G.; Yin, Z. The adenosine monophosphate (amp) analog, 5-aminoimidazole-4-carboxamide ribonucleotide (aicar) inhibits hepatosteatosis and liver tumorigenesis in a high-fat diet murine model treated with diethylnitrosamine (den). Med. Sci. Monit. 2018, 24, 8533–8543. [Google Scholar] [CrossRef] [PubMed]
  127. Zeng, X.X.; Zheng, R.L.; Zhou, T.A.; He, H.Y.; Liu, J.Y.; Zheng, Y.; Tong, A.P.; Xiang, M.L.; Song, X.R.; Yang, S.Y.; et al. Novel thienopyridine derivatives as specific anti-hepatocellular carcinoma (hcc) agents: Synthesis, preliminary structure-activity relationships, and in vitro biological evaluation. Bioorg. Med. Chem. Lett. 2010, 20, 6282–6285. [Google Scholar] [CrossRef]
  128. Zhou, R.; Huang, W.J.; Guo, Z.Y.; Li, L.; Zeng, X.R.; Deng, Y.Q.; Hu, F.Y.; Tong, A.P.; Yang, L.; Yang, J.L. Molecular mechanism of hepatocellular carcinoma-specific antitumor activity of the novel thienopyridine derivative tp58. Oncol. Rep. 2012, 28, 225–231. [Google Scholar]
  129. El-Miligy, M.M.; Rida, S.M.; Ashour, F.A.; Badr, M.H.; El-Bassiony, E.M.; El-Demellawy, M.A.; Omar, A.M. Dual inhibitors of hepatitis c virus and hepatocellular carcinoma: Design, synthesis and docking studies. Fut. Sci. OA 2018, 4, FSO252. [Google Scholar] [CrossRef]
  130. Dai, X.; Wang, L.; Deivasigamni, A.; Looi, C.Y.; Karthikeyan, C.; Trivedi, P.; Chinnathambi, A.; Alharbi, S.A.; Arfuso, F.; Dharmarajan, A.; et al. A novel benzimidazole derivative, mbic inhibits tumor growth and promotes apoptosis via activation of ros-dependent jnk signaling pathway in hepatocellular carcinoma. Oncotarget 2017, 8, 12831–12842. [Google Scholar] [CrossRef]
  131. Schulte, L.; Scheiner, B.; Voigtlander, T.; Koch, S.; Schweitzer, N.; Marhenke, S.; Ivanyi, P.; Manns, M.P.; Rodt, T.; Hinrichs, J.B.; et al. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int. 2019, 39, 714–726. [Google Scholar] [CrossRef]
  132. Seo, Y.S.; Kim, Y.J.; Kim, M.S.; Suh, K.S.; Kim, S.B.; Han, C.J.; Kim, Y.J.; Jang, W.I.; Kang, S.H.; Tchoe, H.J.; et al. Association of metformin use with cancer-specific mortality in hepatocellular carcinoma after curative resection: A nationwide population-based study. Medicine (Baltimore) 2016, 95, e3527. [Google Scholar] [CrossRef]
  133. Bhat, M.; Chaiteerakij, R.; Harmsen, W.S.; Schleck, C.D.; Yang, J.D.; Giama, N.H.; Therneau, T.M.; Gores, G.J.; Roberts, L.R. Metformin does not improve survival in patients with hepatocellular carcinoma. World J. Gastroenterol. 2014, 20, 15750–15755. [Google Scholar] [CrossRef]
  134. Chung, Y.K.; Hwang, S.; Song, G.W.; Lee, Y.J.; Kim, K.H.; Ahn, C.S.; Moon, D.B.; Ha, T.Y.; Jung, D.H.; Park, G.C.; et al. Absence of antitumor effects of metformin in sorafenib-treated patients with hepatocellular carcinoma recurrence after hepatic resection and liver transplantation. Ann. Hepatobiliary Pancreat. Surg. 2018, 22, 297–304. [Google Scholar] [CrossRef] [PubMed]
  135. Casadei Gardini, A.; Faloppi, L.; De Matteis, S.; Foschi, F.G.; Silvestris, N.; Tovoli, F.; Palmieri, V.; Marisi, G.; Brunetti, O.; Vespasiani-Gentilucci, U.; et al. Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale. Eur. J. Cancer 2017, 86, 106–114. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. The structure and the activation of AMP-Activated Protein Kinase (AMPK). AMPK is composed of a catalytic α subunit and two regulatory β and γ subunits. The activation of AMPK relies on AMP-binding to the γ subunit and the phosphorylation of Thr172 on the α subunit regulated by upstream kinases like CaMKKβ and LKB1 and activated AMPK regulates its downstream signal pathways.
Figure 1. The structure and the activation of AMP-Activated Protein Kinase (AMPK). AMPK is composed of a catalytic α subunit and two regulatory β and γ subunits. The activation of AMPK relies on AMP-binding to the γ subunit and the phosphorylation of Thr172 on the α subunit regulated by upstream kinases like CaMKKβ and LKB1 and activated AMPK regulates its downstream signal pathways.
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Figure 2. The schematic of AMPK activators regulate Hepatocellular Carcinoma (HCC) development.
Figure 2. The schematic of AMPK activators regulate Hepatocellular Carcinoma (HCC) development.
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MDPI and ACS Style

Jiang, X.; Tan, H.-Y.; Teng, S.; Chan, Y.-T.; Wang, D.; Wang, N. The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma. Cancers 2019, 11, 647. https://doi.org/10.3390/cancers11050647

AMA Style

Jiang X, Tan H-Y, Teng S, Chan Y-T, Wang D, Wang N. The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma. Cancers. 2019; 11(5):647. https://doi.org/10.3390/cancers11050647

Chicago/Turabian Style

Jiang, Xue, Hor-Yue Tan, Shanshan Teng, Yau-Tuen Chan, Di Wang, and Ning Wang. 2019. "The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma" Cancers 11, no. 5: 647. https://doi.org/10.3390/cancers11050647

APA Style

Jiang, X., Tan, H. -Y., Teng, S., Chan, Y. -T., Wang, D., & Wang, N. (2019). The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma. Cancers, 11(5), 647. https://doi.org/10.3390/cancers11050647

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