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Review

Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications

by
Hyunho Yoon
1 and
Sanghoon Lee
2,*
1
Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon 14662, Korea
2
Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul 02841, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(4), 2170; https://doi.org/10.3390/ijms23042170
Submission received: 29 January 2022 / Revised: 15 February 2022 / Accepted: 15 February 2022 / Published: 16 February 2022
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment 2.0)
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Abstract

:
Ovarian cancer is the most malignant gynecological tumor. Previous studies have reported that metabolic alterations resulting from deregulated lipid metabolism promote ovarian cancer aggressiveness. Lipid metabolism involves the oxidation of fatty acids, which leads to energy generation or new lipid metabolite synthesis. The upregulation of fatty acid synthesis and related signaling promote tumor cell proliferation and migration, and, consequently, lead to poor prognosis. Fatty acid-mediated lipid metabolism in the tumor microenvironment (TME) modulates tumor cell immunity by regulating immune cells, including T cells, B cells, macrophages, and natural killer cells, which play essential roles in ovarian cancer cell survival. Here, the types and sources of fatty acids and their interactions with the TME of ovarian cancer have been reviewed. Additionally, this review focuses on the role of fatty acid metabolism in tumor immunity and suggests that fatty acid and related lipid metabolic pathways are potential therapeutic targets for ovarian cancer.

1. Introduction

Fatty acids are important energy sources and structural components of cells in most species, including humans. Fatty acid oxidation, a lipid metabolic process, is essential for adenosine triphosphate (ATP) production and synthesis of new lipid metabolites [1]. Previous studies have reported that dysregulation of fatty acid metabolism is the etiological factor for various diseases, such as arteriosclerosis, diabetes, and fatty liver [2]. In particular, upregulated levels of fatty acids are associated with an increased risk of developing cancer because they regulate several biological functions, including maintaining the structure of cancer cell membranes and transducing oncogenic signals.
The fatty acid synthase (FASN or FAS) levels and the de novo synthesis of fatty acids are upregulated in several malignancies, such as breast [3], gastric [4], lung [5], liver [6], prostate [7,8], pancreatic [9], esophageal [10], and ovarian cancers [11], to maintain the uncontrolled growth and the increased survival rate of cancer cells. For example, free fatty acids promote estrogen receptor-alpha-positive breast cancer cell proliferation and aggressiveness through the activation of the mTOR pathway [12]. Previous studies have reported that upregulated FASN levels in several cancers are associated with increased fatty acid synthesis and poor prognosis [13]. FASN, a lipogenic enzyme, catalyzes the synthesis of new fatty acids using malonyl-CoA and acetyl-CoA as substrates [13]. Gouw et al. demonstrated that KRAS activated FASN promotes lung cancer cell proliferation [5]. One study evaluated 60, 20, and 10 squamous cell carcinoma, adenocarcinoma, and healthy esophageal tissue samples, respectively. The expression of FASN was detected in 90–95% of squamous cell carcinoma and adenocarcinoma samples, but not in healthy esophageal tissue samples. Additionally, FASN expression was positively correlated with esophageal cancer cell growth, migration, and tumorigenesis [10].
In cancer, fatty acid oxidation also contributes to oncogenic signal transduction, energy production, and cancer cell membrane architecture. MYC or JAK/STAT3-regulated fatty acid oxidation promotes triple-negative breast cancer (TNBC) cell growth, stemness, and chemoresistance, and provides novel therapeutic targets for TNBC [14,15,16]. D-bifunctional protein (DBP) is upregulated in prostate cancer and promotes fatty acid oxidation. Thus, DBP-mediated fatty acid oxidation is considered a potential oncogenic metabolic change that contributes to tumor progression [17]. Additionally, fatty acid oxidation promotes tumor chemoresistance and cell survival under hypoxic conditions. The inhibition of fatty acid oxidation increases the sensitivity of chemo-resistant cancer cells to mTORC1 inhibitors and paclitaxel in lung adenocarcinoma and chronic lymphocytic leukemia [18,19,20]. These studies suggested that fatty acid oxidation is a promising target for overcoming drug resistance in cancer treatment.
Recent studies on the interaction between fatty acids and tumor microenvironment (TME) have revealed that fatty acids play an important role in cancer cell survival by influencing tumor immunity. Fatty acid metabolism-stimulated tumor-infiltrating T lymphocytes enhanced the efficacy of melanoma immunotherapy [21]. Additionally, recent studies have demonstrated that regulatory T cells within tumors exhibit upregulated lipid contents, which resulted from the upregulation of glycolysis to support fatty acid synthesis and cell expansion [22]. These findings suggest that fatty acids alter tumor immunity by modulating the TME, which may be a promising therapeutic target in cancer immunotherapy. This review focuses on the role of fatty acid metabolism and its interaction with the TME of ovarian cancer. The therapeutic potential of fatty acid-associated lipid metabolism for ovarian cancer has also been discussed.

2. Fatty Acids

2.1. Source of Fatty Acids

Fatty acid metabolism is markedly altered in rapidly proliferating tumor cells, which results in increased ATP production [23,24]. Although most healthy cells prefer an exogenous source of fatty acid, tumor cells synthesize new fatty acids. Fatty acids are a major structural component of biological membranes and a component of complex lipids, such as triacylglycerols, membrane phospholipids, and signaling intermediates, including diacylglycerol, phosphoinositols, sphingosine, and phosphatidic acid [25]. These complex lipids are derived from acetyl-CoA, a building block for the de novo synthesis of fatty acids [1]. In the mitochondria, acetyl-CoA is generated from various nutrients, including sugars, proteins, and dietary fats.

2.2. FASN

Functional mammalian FASNs comprise homodimers with a conventional ‘head-to-tail’ structure. Each protein subunit comprises three catalytic domains at the N-terminus (ketoacyl synthetase [KS], malonyl acetyltransferase [MAT], and dehydratase) and four core domains at the C-terminus (enoyl reductase, ketoacyl reductase, acyl carrier protein [ACP], and thioesterase [TE]) [26,27]. The active arrangement of two identical proteins was mainly deduced from experiments with 1,3-dibromo-2-propanone that can crosslink the KS active site (Cys161 thiol) in one monomer with ACP (4′-phosphopantetheine thiol) in the other monomer [28,29]. Additionally, analysis of the catalytic activity of heterodimeric FASN, in which one subunit harbors mutations in all seven functional domains and the structural proximity between KS and MAT within the subunits of FASNs, revealed the formation of two coils in an overlapping arrangement [30,31].
In addition to the typical functions, human FASN plays important roles in the de novo biosynthesis of long-chain fatty acids, such as acetyl-CoA, malonyl-CoA, and 16 carbon (C16) palmitate from NADPH; the TE domain of FASN; and chain length-specific fatty acids, which leads to the release of palmitate through hydrolysis of the acyl-S-phosphopantetheine thioester [32]. The structure of the FASN TE domain is well conserved across species. Cryo-electron microscopy analysis has revealed the high specificity of TE for C16 to C18 fatty acyl substrates [33]. Human TE2, a type II thioesterase, regulates an FASN that promotes the premature release of short fatty acids during hydrolysis. Structural analysis revealed that human TE2 selectively interacts with the ACP domain of FASN, followed by interaction with a 4′-phosphopantetheinyl moiety attached to the ACP structure [34].

2.3. Fatty Acid-Binding Proteins (FABPs)

Studies examining the effect of fatty acids on cells have demonstrated that fatty acids regulate gene expression, growth and survival pathways, and linked signaling pathways for the metabolism of nutrient resources and mediate inflammatory responses [35,36,37]. FABP, a conserved protein, plays a pivotal role in lipid transport and metabolic reactions in various tissues and organs [38]. The FABP family comprises at least nine homologous proteins with specific tissue distribution patterns. These proteins are named primarily according to the tissue in which they are expressed. FABP family members include liver-specific, intestine-specific, heart-specific, adipocyte-specific, epidermis-specific, ileum-specific, brain-specific, myelin sheath-specific, and testis-specific FABPs [39]. The main functions of the cytoplasmic FABPs are to maintain the dynamic processes of cellular lipid metabolism, including lipolysis and peroxisome proliferator-activated receptor-gamma (PPARγ)-mediated adipogenesis. The roles of adipose-specific FABP (A-FABP) and epidermal-specific FABP in the pathogenesis of obesity-related diseases have been previously reported [40]. The expression of A-FABP, which is the best-characterized isoform, is regulated during adipocyte differentiation. Additionally, fatty acids, PPARγ agonists, and insulin regulate the transcription of A-FABP [41,42]. Previous studies focused on the development of high-affinity and selective chemicals targeting A-FABP have demonstrated that A-FABP functions as adipokines in obesity-associated breast cancer and mutant tumor cells with high A-FABP expression levels [43,44]. This indicates that targeting A-FABP is a potential therapeutic strategy for metabolic diseases.

2.4. Fatty Acid Transport Proteins (FATPs)

FATP, a transmembrane transport protein, allows long-chain fatty acids into cells, which, in turn, enhances fatty acid uptake. CD36, a member of FATP, has an extracellular binding site for fatty acids, an intracellular acyl-CoA synthetase active site and an ATP binding domain [45]. Fatty acids transported by CD36 are converted to secondary metabolites such as ceramides, diacylglycols, and inositol phospholipid derivatives. These metabolites play important roles in many biological functions, such as insulin resistance and cholesterol synthesis [46,47]. In addition to its fatty acid transport function, CD36 functions as a receptor for long-chain fatty acids. In taste cells, CD36-mediated linoleic acid inhibits serotonin and dopamine secretion by modulating Src kinase [48]. CD36 has also been implicated in some metabolic diseases, such as diabetes, Alzheimer’s disease, and cancer. For example, blockade of CD36 prevents atherosclerosis progression in high-fat diet mice [49,50]. In breast cancer, CD36 is highly expressed, and some studies have found that CD36 plays an essential role in cancer progression, migration and metastasis by regulating cell cycle and ERK1/2 signaling [51]. This suggests that CD36 could be a potential therapeutic target for treating CD36-related diseases.

3. Alteration of Fatty Acid Metabolism in Ovarian Cancer

3.1. Fatty Acid Metabolism in Ovarian Cancer

Ovarian cancer is one of the most common and malignant cancers among women. Epithelial ovarian cancer, which is the most common type of ovarian cancer that is initiated at the fallopian tube epithelium [52], is generally diagnosed at an advanced stage and is the most common cause of gynecological-related death [53]. Germ cell and stromal cell tumors of ovarian cancer are rare types of non-epithelial tumors, accounting for approximately 5–10% of all ovarian cancers [54,55]. These rare tumors are diagnosed at an early stage in young women and are associated with an improved 5-year survival rate [56,57]. High-grade serous ovarian cancer (HGSOC) is the most common histological type of ovarian cancer [58,59,60]. RNA sequencing (RNA-seq) and microarray data analysis of patients with HGSOC from The Cancer Genome Atlas revealed the following four subtypes of HGSOC based on the gene expression profiles: mesenchymal, immune response, proliferation, and differentiation [60,61]. HGSOC is often characterized by germline mutations in genes, such as those encoding p53 and BRCA. The mutated genes are genetic risk factors for ovarian cancer development [62,63]. Advances in targeted therapies, combination therapies, and immunotherapeutic agents have not markedly contributed to decreasing the death rates of ovarian cancer.
Accumulating studies indicate that plasma levels of fatty acid composition represent potential biomarkers for ovarian and other gynecological cancers [64,65]. Furthermore, recent studies have suggested that alterations in fatty acid metabolism may play a unique role in ovarian cancer pathogenesis and aggressiveness (Figure 1). FASN, which is upregulated in ovarian cancer tissues, is associated with poor prognosis and survival [66]. In ovarian clear cell carcinoma, cancer grade was significantly correlated with FASN expression [66]. Grunt et al. reported that cell membrane FASN-mediated phospholipids interact with receptor tyrosine kinases, including ErbB2 (HER2/neu), which are upregulated in ovarian cancer [67]. This interaction activates the phosphoinositide-3-kinase (PI3K)-mTOR pathway, which promotes the proliferation and survival of ovarian cancer cells [66,67,68]. The upregulated expression of FASN ovarian cancer cell lines and primary cultures increases de novo fatty acid synthesis, cell growth, and cell viability, and enhances chemoresistance to cisplatin [69,70]. These studies suggest that FASN is a metabolic marker for ovarian cancer development and progression.
Stearoyl-CoA desaturase-1 (SCD1) is an endoplasmic reticulum enzyme that catalyzes the synthesis of saturated fatty acids (e.g., oleates and palmitolates) from mono-unsaturated fatty acids (e.g., stearoyl-CoA and palmitoyl-CoA). Previous studies have demonstrated that SCD1 is a biochemical hallmark of cancer cells and that it modulates fatty acid composition in cancer [71]. The expression of SCD1 is upregulated in ovarian cancer stem cells [72]. Treatment with SCD1 inhibitors suppresses the growth of ovarian cancer stem cells in a mouse model. Mechanistic studies revealed that NF-kB can directly regulate the transcription of SCD1 [73]. Additionally, upregulated SCD1 expression levels protected ovarian cells against ferroptosis, an iron-mediated oxidative damage that inhibits the growth of ovarian cancer cells [74,75]. This suggested that targeting SCD1 is a potential therapeutic strategy for ovarian cancer.
Exogenous fatty acid metabolism induced by human adipocytes is also strongly associated with cancer progression and metastasis. Co-culture of human omental adipocytes with ovarian cancer cells promoted the growth, homing, migration, and invasion of ovarian cancer cells by providing fatty acids [76,77]. In omental metastases, FABP4, a type of lipid chaperones, was detected at the interface between adipocytes and tumor cells [78]. FABP4 modulates lipid metabolism of ovarian cancer cells by destroying tumor-infiltrating dendritic cells, thereby interfering with anti-tumor immunity, resulting in poor prognosis of ovarian cancer [76,78]. These studies suggested that FABP4 functions as a key mediator between adipocytes and cancer progression. Thus, FABP4 is a potential therapeutic target for ovarian cancer.

3.2. Fatty Acid Metabolism in the TME of Ovarian Cancer

Adipocytes in the TME serve as a major source of fatty acids. In the TME, adipocyte-derived lipids, including fatty acids, affect cancer cells and various peripheral cells, such as cancer-associated fibroblasts, dendritic cells, macrophages, and immune cells. Cancer cells stimulate adipocytes with inflammatory cytokines, which are closely related to lipid production. Yu et al. demonstrated that interleukin-17A (IL-17A), a pro-inflammatory cytokine, promoted the growth and metastasis of ovarian cancer by regulating fatty acid metabolism in adipocytes, especially regulating fatty acid uptake by cancer cells. Human recombinant IL-17A induces fatty acid uptake by upregulating FABP4 expression in OvCa cells and consequently contributes to the progression and metastasis of ovarian cancer cells [79]. Specifically, IL-17A activated STAT3 phosphorylation to promote FABP4 expression, thereby increasing ovarian cancer cell proliferation. Immune cell-derived cytokines, including IL-1β and transforming growth factor β1 (TGF-β1), are reported to promote the release of saturated fatty acids by stimulating lipolysis in adipocytes. These saturated fatty acids activate TLR4 signaling in macrophages, which leads to the stimulation of the production of pro-inflammatory mediators involved in conferring chemical resistance to the tumor cells [80,81].
Adipokines, such as IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and adiponectin in the ovarian cancer microenvironment can promote cancer cell growth by activating fatty acid production in adipocytes [76]. In addition, adipokines were involved in ovarian follicle development and cancer by regulating PI3K/AKT, AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR) signaling pathways [82]. Additionally, polyunsaturated fatty acids, such as linoleic acid accumulated in the ovarian cancer microenvironment, can activate peroxisome proliferator-activated receptor β/δ (PPARβ/δ) signaling in tumor-associated macrophages (TAMs) [83]. Activation of PPARβ/δ, which belongs to the nuclear receptor group, is one of the hallmarks of cancer [84]. Previous studies have reported that activated PPARβ/δ is a master regulator of adipocyte differentiation and that it modulates fatty acid storage and glucose metabolism [85]. In ovarian cancer, TAMs regulate metabolic function through PPARβ/δ and some signature genes (e.g., LRP5, CD300A, MAP3K8, and ANGPTL4) associated with immune regulation and tumor progression that correlate with short relapse-free survival in serous ovarian cancer [83].
Adipocyte-associated molecules are reported to regulate cancer metastasis by regulating cancer cell metabolism. Miranda et al. demonstrated that salt-inducible kinase 2 (SIK2) has an essential role in adipocyte-induced ovarian cancer metastasis [86,87]. SIK2, which is upregulated in adipocyte-rich metastatic deposits, regulates both phosphatidylinositol 3-kinase (PI3K) and acetyl-CoA carboxylase 1 (ACC1)-mediated fatty acid oxidation and consequently promotes omental metastasis [86]. These studies suggested that lipid metabolism in the TME is regulated by cancer cells, lipid cells, and surrounding cells through a complex process. Therefore, elucidation of the interactions between ovarian cancer cells and surrounding stromal cell types in the ovarian cancer microenvironment will provide useful insights for the development of novel therapeutic approaches for ovarian cancer.

3.3. Fatty Acid-Mediated Ovarian Cancer Immunity

Fatty acids secreted by tumor-associated stromal cells, including adipocytes, may exert tumor-promoting effects on various immune cells, such as macrophages, natural killer (NK) cells, dendritic cells, neutrophils, and T cells recruited to the TME. Reprogramming of lipid metabolism in tumor cells caused by these interactions may provide cells with a survival advantage during cancer progression and metastasis. For example, T cell activation or differentiation is closely related to fatty acid synthesis and oxidation via the mTOR-sterol regulatory element binding protein (SREBP) pathway [88]. Some recent studies have demonstrated that aberrant activation of FASN can impair the anti-tumor immunity in cancer immunotherapy [89]. Jiang et al. reported upregulated levels of unsaturated fatty acids, saturated fatty acids, and triacylglycerols in the ascites of ID8 (mouse ovarian surface epithelial cell line)-bearing mice exhibiting FASN overexpression. In the TME, aberrant lipid accumulation impairs tumor-infiltrating dendritic cells, which leads to the inhibition of anti-tumor T cell infiltration [89]. This suggested that aberrant overexpression of FASN is correlated with immunosuppressive status in ovarian cancer.
The infiltration and differentiation of TAMs are positively correlated with all stages of tumor progression, angiogenesis, and metastasis because they secrete various cytokines and chemokines and regulate the anti-tumor immune responses of T and NK cells [90,91]. Previous studies have revealed a correlation between obesity and ovarian cancer incidence, progression, and metastasis [92]. Liu et al. demonstrated that obesity promotes ovarian cancer metastasis by increasing lipogenesis and decreasing the infiltration of M1 macrophages that initiate an immune response against bacteria and viruses [93,94]. In obesity, the expression of SREBP-1, a transcription factor involved in fatty acid synthesis in ovarian cancer cells, is upregulated, which leads to increased accumulation of new fatty acids and enhanced fatty acid transport [93]. De novo fatty acid synthesis promoted ovarian metastatic potential by increasing vascularity and downregulated the infiltration of M1 macrophages. These findings are not consistent with the previously reported role of macrophages. However, the inverse correlation between M1:M2 ratio of TAMs and tumor stage was reported to be associated with poor overall survival [95]. Further studies are needed to investigate fatty acid and related macrophage-based immune responses in ovarian cancer.

4. Fatty Acid Metabolism-Targeted Therapeutic Strategies for Ovarian Cancer

4.1. FASN Inhibitors

Most cancers depend on the synthesis of new fatty acids. Hence, FASN is a potential therapeutic target for cancer. Previous studies have reported that the inhibition of FASN exerts growth-inhibitory effects on ovarian cancer [96,97]. Treatment with C75 and G28UCM, which are the synthetic inhibitors of FASN, decreased ovarian cancer cell growth, and induced apoptosis [98]. Mechanistic studies revealed that C75 markedly inhibited lipogenesis and downregulated the oncogenic PI3K-AKT signaling pathway [67,99]. Cerulenin, a specific FASN inhibitor, suppresses the expression of HER2/neu in cancer [100]. Treatment with cerulenin markedly inhibited fatty acid biosynthesis in a tumor xenograft model of ovarian cancer and increased the survival rates [101]. Additionally, treatment with cerulenin potentiated the anti-tumor immune responses of cytotoxic T cells and consequently inhibited tumor growth in the xenograft models of ovarian cancer [89]. Thus, cerulenin has potential applications in ovarian cancer immunotherapy. Orlistat, a potent pancreatic lipase inhibitor that was approved by the Food and Drug Administration in 2010 to treat obesity, prevents the absorption of fat from the diet in humans [102]. Previous studies have reported that orlistat exerts growth-inhibitory effects against various cancers by inhibiting FASN [13]. Papaevangelo et al. reported that orlistat inhibited fatty acid metabolism in ovarian cancer cells and that orlistat potentiated the growth-inhibitory effects of cisplatin against platinum-resistant ovarian cancer cells in vivo by inducing apoptosis and necrosis [70]. C93, a FASN inhibitor, inhibited the growth of carboplatin/paclitaxel-resistant ovarian cancer cells [103]. Treatment with C93 induced apoptosis and mitigated cisplatin resistance in ovarian cancer cells [69]. These results suggest that FASN is a potential therapeutic target for ovarian cancer.

4.2. Fatty Acid Uptake Inhibitors

Exogenous fatty acid intake can promote cancer progression and metastasis. Most of these processes are mediated by CD36, low-density lipoprotein receptor, and FABP in the cancer cell membrane, which are potential therapeutic targets for cancer. Preclinical studies have reported that treatment with anti-CD36 antibodies significantly exerted anti-tumor or anti-metastatic effects [104]. Treatment with anti-CD36 monoclonal antibodies decreased tumor burden in mouse xenografts of ovarian cancer [105]. Jayawardhana et al. engineered fatty acid-like Pt(IV) prodrugs (FALPs), which inhibit CD36-dependent fatty acid uptake [106]. FALPs exerted potent-growth-inhibitory effects against cisplatin-resistant ovarian cancer cells by promoting mitochondrial damage [106]. BMS309403, a small-molecule inhibitor of FABPs, including FABP4, competitively inhibits the binding of endogenous fatty acids by interacting with the fatty acid-binding pocket [107]. In ovarian cancer cells, BMS309403 significantly inhibited lipid accumulation and adipocyte-mediated omental metastasis [76]. Additionally, treatment with the FABP4 inhibitor suppressed ovarian cancer cell proliferation and omental colonization and increased the sensitivity of cancer cells to carboplatin [108]. This suggested that targeting the free fatty acid uptake pathway is a potential therapeutic strategy for ovarian cancer.

4.3. Other Inhibitors Targeting Fatty Acid Metabolism

A939572, a potent small-molecule inhibitor of SCD1, induces apoptosis and inhibits the proliferation of cancer cells, including kidney, bladder, liver, colon, and thyroid cancer cells [109,110,111,112]. SCD1, which protects the cancer cells against ferroptosis, is a potential therapeutic target for ovarian cancer. Treatment with A939572 significantly potentiated the growth-inhibitory effects of the ferroptosis inducers RSL3 and erastin on ovarian cancer cells and in vivo xenograft models [75].
The expression of SIK2 is upregulated in adipocyte-rich metastatic deposits in ovarian cancer and is strongly correlated with abdominal metastasis. Zhou et al. examined the effects of ARN-3236, a small-molecule inhibitor of SIK2, on ovarian cell growth in vitro and in vivo [86,113]. Treatment with ARN-3236 decreased ovarian cancer growth and enhanced the response to paclitaxel chemotherapy [113]. This suggested that targeting SIK2 is a potential therapeutic strategy for cancer.
Miranda et al. demonstrated that downregulated levels of AMPK promote peritoneal metastasis of ovarian cancer by activating carnitine palmitoyltransferase 1 (CPT1) through the regulation of acetyl-CoA carboxylase phosphorylation [86]. One study examined the efficacy of a metabolic inhibitor cocktail containing transforming growth factor beta-activated kinase 1 (TAK1) (AMPK activator) and FASN synthase inhibitors against ovarian cancer cells [97]. Treatment with the inhibitor cocktail decreased ovarian cancer metastasis and aggressiveness by inhibiting the mTOR and TAK1 signaling pathways [97]. This indicated that targeting AMPK-mediated lipid metabolism is a potential therapeutic strategy to mitigate peritoneal metastasis in ovarian cancer (Table 1).

5. Conclusions and Perspective

Fatty acid-induced lipid metabolic reprogramming is associated with increased incidence and aggressiveness of ovarian cancer. Several studies have elucidated the mechanisms underlying fatty acid-mediated ovarian cancer progression, recurrence, and metastasis. Adipocyte-derived fatty acids can alter tumor immunity by recruiting immune cells to the TME. This fatty acid-mediated lipid metabolic reprogramming provides survival advantages to tumor cells during therapy and metastasis (Figure 2). Fatty acid metabolism in ovarian cancer is a complex process that includes lipid absorption, lipid synthesis, and fatty acid oxidation. The roles of enzymes involved in fatty acid synthesis and lipid absorption in ovarian cancer pathogenesis and chemoresistance have been characterized. Thus, the modulation of these enzymes is a potential, novel therapeutic strategy for ovarian cancer. Several preclinical and clinical trials targeting these enzymes have demonstrated improved treatment outcomes and prevention of further spread and progression of cancer. However, some FASN inhibitors were associated with neuronal stem cell dysfunction and serious side effects, including decreased food intake and weight loss in mice [114,115]. These findings indicate that regulated crosstalk between ovarian cancer cells and surrounding cells in the TME can modulate lipid metabolic processes by reprogramming fatty acid metabolism and consequently promotes ovarian cancer proliferation, invasion, metastasis, and drug resistance. Although the clinical safety of fatty acid-targeted drugs is a concern, fatty acid and related lipid metabolic pathways are potential therapeutic targets for ovarian cancer.

Author Contributions

H.Y. designed the manuscript; S.L. supervised the project; all authors wrote and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Research Foundation of Korea Grant by the Korean Government, grant number NRF-2016R1C1B3015250 (date of approval: 1 March 2016). This work was also supported by the Catholic University of Korea, Research Fund, 2021.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Currie, E.; Schulze, A.; Zechner, R.; Walther, T.C.; Farese, R.V., Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013, 18, 153–161. [Google Scholar] [CrossRef] [Green Version]
  2. Koundouros, N.; Poulogiannis, G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 2020, 122, 4–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Monaco, M.E. Fatty acid metabolism in breast cancer subtypes. Oncotarget 2017, 8, 29487–29500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Duan, J.; Sun, L.; Huang, H.; Wu, Z.; Wang, L.; Liao, W. Overexpression of fatty acid synthase predicts a poor prognosis for human gastric cancer. Mol. Med. Rep. 2016, 13, 3027–3035. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Gouw, A.M.; Eberlin, L.S.; Margulis, K.; Sullivan, D.K.; Toal, G.G.; Tong, L.; Zare, R.N.; Felsher, D.W. Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proc. Natl. Acad. Sci. USA 2017, 114, 4300–4305. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Raab, S.; Gadault, A.; Very, N.; Decourcelle, A.; Baldini, S.; Schulz, C.; Mortuaire, M.; Lemaire, Q.; Hardiville, S.; Dehennaut, V.; et al. Dual regulation of fatty acid synthase (FASN) expression by O-GlcNAc transferase (OGT) and mTOR pathway in proliferating liver cancer cells. Cell Mol. Life Sci. 2021, 78, 5397–5413. [Google Scholar] [CrossRef]
  7. Swinnen, J.V.; Roskams, T.; Joniau, S.; Van Poppel, H.; Oyen, R.; Baert, L.; Heyns, W.; Verhoeven, G. Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int. J. Cancer 2002, 98, 19–22. [Google Scholar] [CrossRef]
  8. Balaban, S.; Nassar, Z.D.; Zhang, A.Y.; Hosseini-Beheshti, E.; Centenera, M.M.; Schreuder, M.; Lin, H.M.; Aishah, A.; Varney, B.; Liu-Fu, F.; et al. Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer. Mol. Cancer Res. 2019, 17, 949–962. [Google Scholar] [CrossRef]
  9. Nishi, K.; Suzuki, K.; Sawamoto, J.; Tokizawa, Y.; Iwase, Y.; Yumita, N.; Ikeda, T. Inhibition of Fatty Acid Synthesis Induces Apoptosis of Human Pancreatic Cancer Cells. Anticancer Res. 2016, 36, 4655–4660. [Google Scholar] [CrossRef] [Green Version]
  10. Zhou, Y.; Niu, C.; Li, Y.; Gao, B.; Zheng, J.; Guo, X.; Ma, W. Fatty acid synthase expression and esophageal cancer. Mol. Biol. Rep. 2012, 39, 9733–9739. [Google Scholar] [CrossRef]
  11. Ji, Z.; Shen, Y.; Feng, X.; Kong, Y.; Shao, Y.; Meng, J.; Zhang, X.; Yang, G. Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer. Front. Oncol. 2020, 10, 593017. [Google Scholar] [CrossRef] [PubMed]
  12. Madak-Erdogan, Z.; Band, S.; Zhao, Y.C.; Smith, B.P.; Kulkoyluoglu-Cotul, E.; Zuo, Q.; Santaliz Casiano, A.; Wrobel, K.; Rossi, G.; Smith, R.L.; et al. Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling. Cancer Res. 2019, 79, 2494–2510. [Google Scholar] [CrossRef] [Green Version]
  13. Menendez, J.A.; Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 2007, 7, 763–777. [Google Scholar] [CrossRef] [PubMed]
  14. Camarda, R.; Zhou, A.Y.; Kohnz, R.A.; Balakrishnan, S.; Mahieu, C.; Anderton, B.; Eyob, H.; Kajimura, S.; Tward, A.; Krings, G.; et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat. Med. 2016, 22, 427–432. [Google Scholar] [CrossRef] [PubMed]
  15. Wang, T.; Fahrmann, J.F.; Lee, H.; Li, Y.J.; Tripathi, S.C.; Yue, C.; Zhang, C.; Lifshitz, V.; Song, J.; Yuan, Y.; et al. JAK/STAT3-Regulated Fatty Acid beta-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab. 2018, 27, 1357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Casciano, J.C.; Perry, C.; Cohen-Nowak, A.J.; Miller, K.D.; Vande Voorde, J.; Zhang, Q.; Chalmers, S.; Sandison, M.E.; Liu, Q.; Hedley, A.; et al. MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer. Br. J. Cancer 2020, 122, 868–884. [Google Scholar] [CrossRef]
  17. Zha, S.; Ferdinandusse, S.; Hicks, J.L.; Denis, S.; Dunn, T.A.; Wanders, R.J.; Luo, J.; De Marzo, A.M.; Isaacs, W.B. Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer. Prostate 2005, 63, 316–323. [Google Scholar] [CrossRef]
  18. Qu, Q.; Zeng, F.; Liu, X.; Wang, Q.J.; Deng, F. Fatty acid oxidation and carnitine palmitoyltransferase I: Emerging therapeutic targets in cancer. Cell Death Dis. 2016, 7, e2226. [Google Scholar] [CrossRef]
  19. Li, J.; Zhao, S.; Zhou, X.; Zhang, T.; Zhao, L.; Miao, P.; Song, S.; Sun, X.; Liu, J.; Zhao, X.; et al. Inhibition of lipolysis by mercaptoacetate and etomoxir specifically sensitize drug-resistant lung adenocarcinoma cell to paclitaxel. PLoS ONE 2013, 8, e74623. [Google Scholar] [CrossRef]
  20. Tung, S.; Shi, Y.; Wong, K.; Zhu, F.; Gorczynski, R.; Laister, R.C.; Minden, M.; Blechert, A.K.; Genzel, Y.; Reichl, U.; et al. PPARalpha and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. Blood 2013, 122, 969–980. [Google Scholar] [CrossRef]
  21. Zhang, Y.; Kurupati, R.; Liu, L.; Zhou, X.Y.; Zhang, G.; Hudaihed, A.; Filisio, F.; Giles-Davis, W.; Xu, X.; Karakousis, G.C.; et al. Enhancing CD8(+) T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 2017, 32, 377–391.e9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Pacella, I.; Procaccini, C.; Focaccetti, C.; Miacci, S.; Timperi, E.; Faicchia, D.; Severa, M.; Rizzo, F.; Coccia, E.M.; Bonacina, F.; et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc. Natl. Acad. Sci. USA 2018, 115, E6546–E6555. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. DeBerardinis, R.J.; Thompson, C.B. Cellular metabolism and disease: What do metabolic outliers teach us? Cell 2012, 148, 1132–1144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Santos, C.R.; Schulze, A. Lipid metabolism in cancer. FEBS J. 2012, 279, 2610–2623. [Google Scholar] [CrossRef] [PubMed]
  25. Beloribi-Djefaflia, S.; Vasseur, S.; Guillaumond, F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 2016, 5, e189. [Google Scholar] [CrossRef] [PubMed]
  26. Smith, S. The animal fatty acid synthase: One gene, one polypeptide, seven enzymes. FASEB J. 1994, 8, 1248–1259. [Google Scholar] [CrossRef]
  27. Jayakumar, A.; Chirala, S.S.; Wakil, S.J. Human fatty acid synthase: Assembling recombinant halves of the fatty acid synthase subunit protein reconstitutes enzyme activity. Proc. Natl. Acad. Sci. USA 1997, 94, 12326–12330. [Google Scholar] [CrossRef] [Green Version]
  28. Stoops, J.K.; Wakil, S.J. Animal fatty acid synthetase. Identification of the residues comprising the novel arrangement of the beta-ketoacyl synthetase site and their role in its cold inactivation. J. Biol. Chem. 1982, 257, 3230–3235. [Google Scholar] [CrossRef]
  29. Witkowski, A.; Joshi, A.K.; Rangan, V.S.; Falick, A.M.; Witkowska, H.E.; Smith, S. Dibromopropanone cross-linking of the phosphopantetheine and active-site cysteine thiols of the animal fatty acid synthase can occur both inter- and intrasubunit. Reevaluation of the side-by-side, antiparallel subunit model. J. Biol. Chem. 1999, 274, 11557–11563. [Google Scholar] [CrossRef] [Green Version]
  30. Joshi, A.K.; Rangan, V.S.; Witkowski, A.; Smith, S. Engineering of an active animal fatty acid synthase dimer with only one competent subunit. Chem. Biol. 2003, 10, 169–173. [Google Scholar] [CrossRef] [Green Version]
  31. Asturias, F.J.; Chadick, J.Z.; Cheung, I.K.; Stark, H.; Witkowski, A.; Joshi, A.K.; Smith, S. Structure and molecular organization of mammalian fatty acid synthase. Nat. Struct. Mol. Biol. 2005, 12, 225–232. [Google Scholar] [CrossRef] [PubMed]
  32. Singh, N.; Wakil, S.J.; Stoops, J.K. On the question of half- or full-site reactivity of animal fatty acid synthetase. J. Biol. Chem. 1984, 259, 3605–3611. [Google Scholar] [CrossRef]
  33. Chakravarty, B.; Gu, Z.; Chirala, S.S.; Wakil, S.J.; Quiocho, F.A. Human fatty acid synthase: Structure and substrate selectivity of the thioesterase domain. Proc. Natl. Acad. Sci. USA 2004, 101, 15567–15572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Ritchie, M.K.; Johnson, L.C.; Clodfelter, J.E.; Pemble, C.W.t.; Fulp, B.E.; Furdui, C.M.; Kridel, S.J.; Lowther, W.T. Crystal Structure and Substrate Specificity of Human Thioesterase 2: Insights Into the Molecular Basis for the Modulation of Fatty Acid Synthase. J. Biol. Chem. 2016, 291, 3520–3530. [Google Scholar] [CrossRef] [Green Version]
  35. Saltiel, A.R.; Kahn, C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001, 414, 799–806. [Google Scholar] [CrossRef] [PubMed]
  36. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 2006, 444, 860–867. [Google Scholar] [CrossRef] [PubMed]
  37. Serhan, C.N. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu. Rev. Immunol. 2007, 25, 101–137. [Google Scholar] [CrossRef] [Green Version]
  38. Storch, J.; Corsico, B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu. Rev. Nutr. 2008, 28, 73–95. [Google Scholar] [CrossRef]
  39. Furuhashi, M.; Hotamisligil, G.S. Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets. Nat. Rev. Drug Discov. 2008, 7, 489–503. [Google Scholar] [CrossRef] [Green Version]
  40. Hotamisligil, G.S.; Bernlohr, D.A. Metabolic functions of FABPs—Mechanisms and therapeutic implications. Nat. Rev. Endocrinol. 2015, 11, 592–605. [Google Scholar] [CrossRef] [Green Version]
  41. Haunerland, N.H.; Spener, F. Fatty acid-binding proteins—Insights from genetic manipulations. Prog. Lipid Res. 2004, 43, 328–349. [Google Scholar] [CrossRef]
  42. Makowski, L.; Hotamisligil, G.S. The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr. Opin. Lipidol. 2005, 16, 543–548. [Google Scholar] [CrossRef] [Green Version]
  43. Cao, H.; Sekiya, M.; Ertunc, M.E.; Burak, M.F.; Mayers, J.R.; White, A.; Inouye, K.; Rickey, L.M.; Ercal, B.C.; Furuhashi, M.; et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 2013, 17, 768–778. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Hao, J.; Yan, F.; Zhang, Y.; Triplett, A.; Zhang, Y.; Schultz, D.A.; Sun, Y.; Zeng, J.; Silverstein, K.A.T.; Zheng, Q.; et al. Expression of Adipocyte/Macrophage Fatty Acid-Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression. Cancer Res. 2018, 78, 2343–2355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Pepino, M.Y.; Kuda, O.; Samovski, D.; Abumrad, N.A. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu. Rev. Nutr. 2014, 34, 281–303. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Petersen, M.C.; Shulman, G.I. Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance. Trends Pharm. Sci. 2017, 38, 649–665. [Google Scholar] [CrossRef] [PubMed]
  47. Garcia-Arribas, A.B.; Alonso, A.; Goni, F.M. Cholesterol interactions with ceramide and sphingomyelin. Chem. Phys. Lipids 2016, 199, 26–34. [Google Scholar] [CrossRef]
  48. El-Yassimi, A.; Hichami, A.; Besnard, P.; Khan, N.A. Linoleic acid induces calcium signaling, Src kinase phosphorylation, and neurotransmitter release in mouse CD36-positive gustatory cells. J. Biol. Chem. 2008, 283, 12949–12959. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Febbraio, M.; Podrez, E.A.; Smith, J.D.; Hajjar, D.P.; Hazen, S.L.; Hoff, H.F.; Sharma, K.; Silverstein, R.L. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Investig. 2000, 105, 1049–1056. [Google Scholar] [CrossRef] [Green Version]
  50. Guy, E.; Kuchibhotla, S.; Silverstein, R.; Febbraio, M. Continued inhibition of atherosclerotic lesion development in long term Western diet fed CD36o /apoEo mice. Atherosclerosis 2007, 192, 123–130. [Google Scholar] [CrossRef]
  51. Liang, Y.; Han, H.; Liu, L.; Duan, Y.; Yang, X.; Ma, C.; Zhu, Y.; Han, J.; Li, X.; Chen, Y. CD36 plays a critical role in proliferation, migration and tamoxifen-inhibited growth of ER-positive breast cancer cells. Oncogenesis 2018, 7, 98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Kurman, R.J.; Shih Ie, M. The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. Am. J. Surg. Pathol. 2010, 34, 433–443. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Lheureux, S.; Gourley, C.; Vergote, I.; Oza, A.M. Epithelial ovarian cancer. Lancet 2019, 393, 1240–1253. [Google Scholar] [CrossRef] [Green Version]
  54. Jayson, G.C.; Kohn, E.C.; Kitchener, H.C.; Ledermann, J.A. Ovarian cancer. Lancet 2014, 384, 1376–1388. [Google Scholar] [CrossRef]
  55. Torre, L.A.; Trabert, B.; DeSantis, C.E.; Miller, K.D.; Samimi, G.; Runowicz, C.D.; Gaudet, M.M.; Jemal, A.; Siegel, R.L. Ovarian cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 284–296. [Google Scholar] [CrossRef] [PubMed]
  56. Gershenson, D.M. Management of ovarian germ cell tumors. J. Clin. Oncol. 2007, 25, 2938–2943. [Google Scholar] [CrossRef]
  57. Colombo, N.; Parma, G.; Zanagnolo, V.; Insinga, A. Management of ovarian stromal cell tumors. J. Clin. Oncol. 2007, 25, 2944–2951. [Google Scholar] [CrossRef]
  58. Shih Ie, M.; Kurman, R.J. Ovarian tumorigenesis: A proposed model based on morphological and molecular genetic analysis. Am. J. Pathol. 2004, 164, 1511–1518. [Google Scholar] [CrossRef]
  59. Olivier, R.I.; van Beurden, M.; Lubsen, M.A.; Rookus, M.A.; Mooij, T.M.; van de Vijver, M.J.; van’t Veer, L.J. Clinical outcome of prophylactic oophorectomy in BRCA1/BRCA2 mutation carriers and events during follow-up. Br. J. Cancer 2004, 90, 1492–1497. [Google Scholar] [CrossRef]
  60. Xie, W.; Sun, H.; Li, X.; Lin, F.; Wang, Z.; Wang, X. Ovarian cancer: Epigenetics, drug resistance, and progression. Cancer Cell Int. 2021, 21, 434. [Google Scholar] [CrossRef]
  61. Murakami, R.; Matsumura, N.; Mandai, M.; Yoshihara, K.; Tanabe, H.; Nakai, H.; Yamanoi, K.; Abiko, K.; Yoshioka, Y.; Hamanishi, J.; et al. Establishment of a Novel Histopathological Classification of High-Grade Serous Ovarian Carcinoma Correlated with Prognostically Distinct Gene Expression Subtypes. Am. J. Pathol. 2016, 186, 1103–1113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Alsop, K.; Fereday, S.; Meldrum, C.; deFazio, A.; Emmanuel, C.; George, J.; Dobrovic, A.; Birrer, M.J.; Webb, P.M.; Stewart, C.; et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol. 2012, 30, 2654–2663. [Google Scholar] [CrossRef] [Green Version]
  63. Tomczak, K.; Czerwinska, P.; Wiznerowicz, M. The Cancer Genome Atlas (TCGA): An immeasurable source of knowledge. Contemp Oncol. 2015, 19, A68–A77. [Google Scholar] [CrossRef] [PubMed]
  64. Xu, Y.; Shen, Z.; Wiper, D.W.; Wu, M.; Morton, R.E.; Elson, P.; Kennedy, A.W.; Belinson, J.; Markman, M.; Casey, G. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 1998, 280, 719–723. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Shen, Z.; Wu, M.; Elson, P.; Kennedy, A.W.; Belinson, J.; Casey, G.; Xu, Y. Fatty acid composition of lysophosphatidic acid and lysophosphatidylinositol in plasma from patients with ovarian cancer and other gynecological diseases. Gynecol. Oncol. 2001, 83, 25–30. [Google Scholar] [CrossRef]
  66. Cai, Y.; Wang, J.; Zhang, L.; Wu, D.; Yu, D.; Tian, X.; Liu, J.; Jiang, X.; Shen, Y.; Zhang, L.; et al. Expressions of fatty acid synthase and HER2 are correlated with poor prognosis of ovarian cancer. Med. Oncol. 2015, 32, 391. [Google Scholar] [CrossRef] [Green Version]
  67. Grunt, T.W.; Wagner, R.; Grusch, M.; Berger, W.; Singer, C.F.; Marian, B.; Zielinski, C.C.; Lupu, R. Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. BioChem. Biophys. Res. Commun. 2009, 385, 454–459. [Google Scholar] [CrossRef]
  68. Wagner, R.; Stubiger, G.; Veigel, D.; Wuczkowski, M.; Lanzerstorfer, P.; Weghuber, J.; Karteris, E.; Nowikovsky, K.; Wilfinger-Lutz, N.; Singer, C.F.; et al. Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells. Oncotarget 2017, 8, 11600–11613. [Google Scholar] [CrossRef] [Green Version]
  69. Bauerschlag, D.O.; Maass, N.; Leonhardt, P.; Verburg, F.A.; Pecks, U.; Zeppernick, F.; Morgenroth, A.; Mottaghy, F.M.; Tolba, R.; Meinhold-Heerlein, I.; et al. Fatty acid synthase overexpression: Target for therapy and reversal of chemoresistance in ovarian cancer. J. Transl. Med. 2015, 13, 146. [Google Scholar] [CrossRef] [Green Version]
  70. Papaevangelou, E.; Almeida, G.S.; Box, C.; deSouza, N.M.; Chung, Y.L. The effect of FASN inhibition on the growth and metabolism of a cisplatin-resistant ovarian carcinoma model. Int. J. Cancer 2018, 143, 992–1002. [Google Scholar] [CrossRef]
  71. Igal, R.A. Stearoyl CoA desaturase-1: New insights into a central regulator of cancer metabolism. Biochim. Biophys. Acta 2016, 1861, 1865–1880. [Google Scholar] [CrossRef] [PubMed]
  72. Roongta, U.V.; Pabalan, J.G.; Wang, X.; Ryseck, R.P.; Fargnoli, J.; Henley, B.J.; Yang, W.P.; Zhu, J.; Madireddi, M.T.; Lawrence, R.M.; et al. Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy. Mol. Cancer Res. 2011, 9, 1551–1561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Li, J.; Condello, S.; Thomes-Pepin, J.; Ma, X.; Xia, Y.; Hurley, T.D.; Matei, D.; Cheng, J.X. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell 2017, 20, 303–314.e305. [Google Scholar] [CrossRef] [Green Version]
  74. Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascon, S.; Hatzios, S.K.; Kagan, V.E.; et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017, 171, 273–285. [Google Scholar] [CrossRef] [Green Version]
  75. Tesfay, L.; Paul, B.T.; Konstorum, A.; Deng, Z.; Cox, A.O.; Lee, J.; Furdui, C.M.; Hegde, P.; Torti, F.M.; Torti, S.V. Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death. Cancer Res. 2019, 79, 5355–5366. [Google Scholar] [CrossRef]
  76. Nieman, K.M.; Kenny, H.A.; Penicka, C.V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M.R.; Romero, I.L.; Carey, M.S.; Mills, G.B.; Hotamisligil, G.S.; et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 2011, 17, 1498–1503. [Google Scholar] [CrossRef] [Green Version]
  77. Leinster, D.A.; Kulbe, H.; Everitt, G.; Thompson, R.; Perretti, M.; Gavins, F.N.; Cooper, D.; Gould, D.; Ennis, D.P.; Lockley, M.; et al. The peritoneal tumour microenvironment of high-grade serous ovarian cancer. J. Pathol. 2012, 227, 136–145. [Google Scholar] [CrossRef] [Green Version]
  78. Gharpure, K.M.; Pradeep, S.; Sans, M.; Rupaimoole, R.; Ivan, C.; Wu, S.Y.; Bayraktar, E.; Nagaraja, A.S.; Mangala, L.S.; Zhang, X.; et al. FABP4 as a key determinant of metastatic potential of ovarian cancer. Nat. Commun. 2018, 9, 2923. [Google Scholar] [CrossRef] [Green Version]
  79. Yu, C.; Niu, X.; Du, Y.; Chen, Y.; Liu, X.; Xu, L.; Iwakura, Y.; Ma, X.; Li, Y.; Yao, Z.; et al. IL-17A promotes fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer growth in an adipocyte-rich microenvironment. Cancer Immunol. Immunother. 2020, 69, 115–126. [Google Scholar] [CrossRef]
  80. Huang, S.; Rutkowsky, J.M.; Snodgrass, R.G.; Ono-Moore, K.D.; Schneider, D.A.; Newman, J.W.; Adams, S.H.; Hwang, D.H. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J. Lipid Res. 2012, 53, 2002–2013. [Google Scholar] [CrossRef] [Green Version]
  81. Caer, C.; Rouault, C.; Le Roy, T.; Poitou, C.; Aron-Wisnewsky, J.; Torcivia, A.; Bichet, J.C.; Clement, K.; Guerre-Millo, M.; Andre, S. Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue. Sci. Rep. 2017, 7, 3000. [Google Scholar] [CrossRef] [PubMed]
  82. Dupont, J.; Reverchon, M.; Cloix, L.; Froment, P.; Rame, C. Involvement of adipokines, AMPK, PI3K and the PPAR signaling pathways in ovarian follicle development and cancer. Int. J. Dev. Biol. 2012, 56, 959–967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Schumann, T.; Adhikary, T.; Wortmann, A.; Finkernagel, F.; Lieber, S.; Schnitzer, E.; Legrand, N.; Schober, Y.; Nockher, W.A.; Toth, P.M.; et al. Deregulation of PPARbeta/delta target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment. Oncotarget 2015, 6, 13416–13433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Wagner, N.; Wagner, K.D. PPAR Beta/Delta and the Hallmarks of Cancer. Cells 2020, 9, 1133. [Google Scholar] [CrossRef] [PubMed]
  85. Ahmadian, M.; Suh, J.M.; Hah, N.; Liddle, C.; Atkins, A.R.; Downes, M.; Evans, R.M. PPARgamma signaling and metabolism: The good, the bad and the future. Nat. Med. 2013, 19, 557–566. [Google Scholar] [CrossRef] [Green Version]
  86. Miranda, F.; Mannion, D.; Liu, S.; Zheng, Y.; Mangala, L.S.; Redondo, C.; Herrero-Gonzalez, S.; Xu, R.; Taylor, C.; Chedom, D.F.; et al. Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche. Cancer Cell 2016, 30, 273–289. [Google Scholar] [CrossRef]
  87. Motohara, T.; Masuda, K.; Morotti, M.; Zheng, Y.; El-Sahhar, S.; Chong, K.Y.; Wietek, N.; Alsaadi, A.; Karaminejadranjbar, M.; Hu, Z.; et al. An evolving story of the metastatic voyage of ovarian cancer cells: Cellular and molecular orchestration of the adipose-rich metastatic microenvironment. Oncogene 2019, 38, 2885–2898. [Google Scholar] [CrossRef] [Green Version]
  88. Lochner, M.; Berod, L.; Sparwasser, T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 2015, 36, 81–91. [Google Scholar] [CrossRef]
  89. Jiang, L.; Fang, X.; Wang, H.; Li, D.; Wang, X. Ovarian Cancer-Intrinsic Fatty Acid Synthase Prevents Anti-tumor Immunity by Disrupting Tumor-Infiltrating Dendritic Cells. Front. Immunol. 2018, 9, 2927. [Google Scholar] [CrossRef] [Green Version]
  90. Noy, R.; Pollard, J.W. Tumor-associated macrophages: From mechanisms to therapy. Immunity 2014, 41, 49–61. [Google Scholar] [CrossRef] [Green Version]
  91. Cassetta, L.; Kitamura, T. Macrophage targeting: Opening new possibilities for cancer immunotherapy. Immunology 2018, 155, 285–293. [Google Scholar] [CrossRef]
  92. Clarke, M.A. It’s not just size that matters: Challenges in studying obesity and female-specific cancers. Lancet Reg. Health West. Pac. 2021, 11, 100164. [Google Scholar] [CrossRef]
  93. Liu, Y.; Metzinger, M.N.; Lewellen, K.A.; Cripps, S.N.; Carey, K.D.; Harper, E.I.; Shi, Z.; Tarwater, L.; Grisoli, A.; Lee, E.; et al. Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages. Cancer Res. 2015, 75, 5046–5057. [Google Scholar] [CrossRef] [Green Version]
  94. Orecchioni, M.; Ghosheh, Y.; Pramod, A.B.; Ley, K. Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS-) vs. Alternatively Activated Macrophages. Front. Immunol. 2019, 10, 1084. [Google Scholar] [CrossRef]
  95. Zhang, M.; He, Y.; Sun, X.; Li, Q.; Wang, W.; Zhao, A.; Di, W. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J. Ovarian Res. 2014, 7, 19. [Google Scholar] [CrossRef] [Green Version]
  96. Lu, T.; Schubert, C.; Cummings, M.D.; Bignan, G.; Connolly, P.J.; Smans, K.; Ludovici, D.; Parker, M.H.; Meyer, C.; Rocaboy, C.; et al. Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy. Bioorg. Med. Chem. Lett 2018, 28, 2159–2164. [Google Scholar] [CrossRef]
  97. Chen, R.R.; Yung, M.M.H.; Xuan, Y.; Zhan, S.; Leung, L.L.; Liang, R.R.; Leung, T.H.Y.; Yang, H.; Xu, D.; Sharma, R.; et al. Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells. Commun. Biol. 2019, 2, 281. [Google Scholar] [CrossRef]
  98. Veigel, D.; Wagner, R.; Stubiger, G.; Wuczkowski, M.; Filipits, M.; Horvat, R.; Benhamu, B.; Lopez-Rodriguez, M.L.; Leisser, A.; Valent, P.; et al. Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells. Int. J. Cancer 2015, 136, 2078–2090. [Google Scholar] [CrossRef] [Green Version]
  99. Tomek, K.; Wagner, R.; Varga, F.; Singer, C.F.; Karlic, H.; Grunt, T.W. Blockade of fatty acid synthase induces ubiquitination and degradation of phosphoinositide-3-kinase signaling proteins in ovarian cancer. Mol. Cancer Res. 2011, 9, 1767–1779. [Google Scholar] [CrossRef] [Green Version]
  100. Menendez, J.A.; Vellon, L.; Mehmi, I.; Oza, B.P.; Ropero, S.; Colomer, R.; Lupu, R. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl. Acad. Sci. USA 2004, 101, 10715–10720. [Google Scholar] [CrossRef] [Green Version]
  101. Pizer, E.S.; Wood, F.D.; Heine, H.S.; Romantsev, F.E.; Pasternack, G.R.; Kuhajda, F.P. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res. 1996, 56, 1189–1193. [Google Scholar]
  102. Padwal, R.S.; Majumdar, S.R. Drug treatments for obesity: Orlistat, sibutramine, and rimonabant. Lancet 2007, 369, 71–77. [Google Scholar] [CrossRef]
  103. Ueda, S.M.; Yap, K.L.; Davidson, B.; Tian, Y.; Murthy, V.; Wang, T.L.; Visvanathan, K.; Kuhajda, F.P.; Bristow, R.E.; Zhang, H.; et al. Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas. J. Oncol. 2010, 2010, 285191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Pascual, G.; Avgustinova, A.; Mejetta, S.; Martin, M.; Castellanos, A.; Attolini, C.S.; Berenguer, A.; Prats, N.; Toll, A.; Hueto, J.A.; et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 2017, 541, 41–45. [Google Scholar] [CrossRef]
  105. Ladanyi, A.; Mukherjee, A.; Kenny, H.A.; Johnson, A.; Mitra, A.K.; Sundaresan, S.; Nieman, K.M.; Pascual, G.; Benitah, S.A.; Montag, A.; et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 2018, 37, 2285–2301. [Google Scholar] [CrossRef] [PubMed]
  106. Jayawardhana, A.; Stilgenbauer, M.; Datta, P.; Qiu, Z.; McKenzie, S.; Wang, H.; Bowers, D.; Kurokawa, M.; Zheng, Y.R. Fatty acid-like Pt(IV) prodrugs overcome cisplatin resistance in ovarian cancer by harnessing CD36. Chem. Commun. 2020, 56, 10706–10709. [Google Scholar] [CrossRef] [PubMed]
  107. Furuhashi, M.; Tuncman, G.; Gorgun, C.Z.; Makowski, L.; Atsumi, G.; Vaillancourt, E.; Kono, K.; Babaev, V.R.; Fazio, S.; Linton, M.F.; et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 2007, 447, 959–965. [Google Scholar] [CrossRef] [Green Version]
  108. Mukherjee, A.; Chiang, C.Y.; Daifotis, H.A.; Nieman, K.M.; Fahrmann, J.F.; Lastra, R.R.; Romero, I.L.; Fiehn, O.; Lengyel, E. Adipocyte-Induced FABP4 Expression in Ovarian Cancer Cells Promotes Metastasis and Mediates Carboplatin Resistance. Cancer Res. 2020, 80, 1748–1761. [Google Scholar] [CrossRef] [Green Version]
  109. Von Roemeling, C.A.; Marlow, L.A.; Wei, J.J.; Cooper, S.J.; Caulfield, T.R.; Wu, K.; Tan, W.W.; Tun, H.W.; Copland, J.A. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Clin. Cancer Res. 2013, 19, 2368–2380. [Google Scholar] [CrossRef] [Green Version]
  110. Piao, C.; Cui, X.; Zhan, B.; Li, J.; Li, Z.; Li, Z.; Liu, X.; Bi, J.; Zhang, Z.; Kong, C. Inhibition of stearoyl CoA desaturase-1 activity suppresses tumour progression and improves prognosis in human bladder cancer. J. Cell Mol. Med. 2019, 23, 2064–2076. [Google Scholar] [CrossRef]
  111. Chen, L.; Ren, J.; Yang, L.; Li, Y.; Fu, J.; Li, Y.; Tian, Y.; Qiu, F.; Liu, Z.; Qiu, Y. Stearoyl-CoA desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis. Sci. Rep. 2016, 6, 19665. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. von Roemeling, C.A.; Marlow, L.A.; Pinkerton, A.B.; Crist, A.; Miller, J.; Tun, H.W.; Smallridge, R.C.; Copland, J.A. Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl CoA desaturase 1 as a novel therapeutic target. J. Clin. Endocrinol. Metab. 2015, 100, E697–E709. [Google Scholar] [CrossRef] [PubMed]
  113. Zhou, J.; Alfraidi, A.; Zhang, S.; Santiago-O’Farrill, J.M.; Yerramreddy Reddy, V.K.; Alsaadi, A.; Ahmed, A.A.; Yang, H.; Liu, J.; Mao, W.; et al. A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel. Clin. Cancer Res. 2017, 23, 1945–1954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Knobloch, M.; Braun, S.M.; Zurkirchen, L.; von Schoultz, C.; Zamboni, N.; Arauzo-Bravo, M.J.; Kovacs, W.J.; Karalay, O.; Suter, U.; Machado, R.A.; et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 2013, 493, 226–230. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Loftus, T.M.; Jaworsky, D.E.; Frehywot, G.L.; Townsend, C.A.; Ronnett, G.V.; Lane, M.D.; Kuhajda, F.P. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000, 288, 2379–2381. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Fatty acid metabolism in the TME of ovarian cancer. Fatty acid-mediated lipid metabolism in TME is well controlled by cancer cells, adipocytes, and stromal cells with complex processes, leading to ovarian cancer metastasis and drug resistance. CAF, cancer-associated fibroblast; NK cell, natural killer cell; TAM, tumor-associated fibroblast; DC, dendritic cell; SREBP-1, sterol regulatory element binding protein 1; FABP, fatty acid binding protein; FASN, fatty acid synthase; SIK2, salt-inducible kinase 2; MCP-1, monocyte chemoattractant protein-1; TIMP-1, tissue inhibitor of metalloproteinase-1; and TGF-β1, transforming growth factor β1.
Figure 1. Fatty acid metabolism in the TME of ovarian cancer. Fatty acid-mediated lipid metabolism in TME is well controlled by cancer cells, adipocytes, and stromal cells with complex processes, leading to ovarian cancer metastasis and drug resistance. CAF, cancer-associated fibroblast; NK cell, natural killer cell; TAM, tumor-associated fibroblast; DC, dendritic cell; SREBP-1, sterol regulatory element binding protein 1; FABP, fatty acid binding protein; FASN, fatty acid synthase; SIK2, salt-inducible kinase 2; MCP-1, monocyte chemoattractant protein-1; TIMP-1, tissue inhibitor of metalloproteinase-1; and TGF-β1, transforming growth factor β1.
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Figure 2. Fatty acid metabolism in the TME of ovarian cancer. Fatty acid-mediated lipid metabolism in TME is well controlled by cancer cells, adipocytes and stromal cells with complex processes, leading to ovarian cancer metastasis and drug resistance. CAF, cancer-associated fibroblast; NK cell, natural killer cell; TAM, tumor-associated fibroblast; DC, dendritic cell; SREBP-1, sterol regulatory element binding protein 1; FABP, fatty acid binding protein; FASN, fatty acid synthase; SIK2, salt-inducible kinase 2; MCP-1, monocyte chemoattractant protein-1; TIMP-1, tissue inhibitor of metalloproteinase-1; TGF-β1, transforming growth factor β1.
Figure 2. Fatty acid metabolism in the TME of ovarian cancer. Fatty acid-mediated lipid metabolism in TME is well controlled by cancer cells, adipocytes and stromal cells with complex processes, leading to ovarian cancer metastasis and drug resistance. CAF, cancer-associated fibroblast; NK cell, natural killer cell; TAM, tumor-associated fibroblast; DC, dendritic cell; SREBP-1, sterol regulatory element binding protein 1; FABP, fatty acid binding protein; FASN, fatty acid synthase; SIK2, salt-inducible kinase 2; MCP-1, monocyte chemoattractant protein-1; TIMP-1, tissue inhibitor of metalloproteinase-1; TGF-β1, transforming growth factor β1.
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Table
Table 1. Therapeutic strategies targeting fatty acid metabolism for ovarian cancer.
Table 1. Therapeutic strategies targeting fatty acid metabolism for ovarian cancer.
DrugEffects and FeaturesReferences
Fatty acid synthase inhibitorsC75 Abrogating lipogenesis; downregulating PI3K-AKT signaling pathway; antitumor effects[67,98,99]
G28UCMDecreasing cell growth and inducing apoptosis[98]
CeruleninAlso known as an inhibitor of HER2/neu; inhibiting fatty acid biosynthesis in a xenograft model; enhancing antitumor immunity of T cells; inhibiting tumor growth and increasing mice survival[89,100,101]
OrlistatPotent inhibitor of pancreatic lipase; FDA-approved for anti-obesity; abolishing fatty acid metabolism; combination treatment with cisplatin enhanced in vivo efficacy[13,70]
C93Inhibiting growth of carboplatin/paclitaxel-resistant ovarian cancer cells; re-sensitizing cisplatin resistant cancer cells; antitumor effects in ovarian cancer[69,103]
Fatty acid uptake inhibitorsAnti-CD36 monoclonal antibodySignificant anti-tumor or anti-metastatic efficacy in preclinical studies; reduced tumor burden in mouse xenografts of ovarian cancer[104,105]
FALPsInhibiting CD36-dependant fatty acid uptake; increased mitochondrial damage by FALPs decreased cell growth in cisplatin-resistant ovarian cancer cells[106]
BMS309403Small molecule inhibitor of fatty acid binding proteins; competitive inhibitors of the binding of endogenous fatty acids; reducing adipocyte-mediated omental metastasis; increasing the sensitivity of ovarian cancer cells to carboplatin[76,107,108]
Other inhibitors targeting fatty acid metabolismA939572Potent small molecule inhibitor of SCD1; enhancing the anticancer effects of the feroptosis inducers, RSL3 and erastin, on ovarian cancer cells and in vivo xenograft models[75]
ARN-3236Small molecule inhibitor of SIK2; Inhibiting ovarian cell growth in vitro and in vivo; showing improved response to paclitaxel chemotherapy[86,113]
TAK1AMPK activator and fatty acid synthase inhibitor; reducing ovarian cancer metastasis by inhibiting mTOR and TAK1 signaling pathway[86,97]
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Yoon, H.; Lee, S. Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications. Int. J. Mol. Sci. 2022, 23, 2170. https://doi.org/10.3390/ijms23042170

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Yoon H, Lee S. Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications. International Journal of Molecular Sciences. 2022; 23(4):2170. https://doi.org/10.3390/ijms23042170

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Yoon, Hyunho, and Sanghoon Lee. 2022. "Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications" International Journal of Molecular Sciences 23, no. 4: 2170. https://doi.org/10.3390/ijms23042170

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