The Implication of Autophagy in Gastric Cancer Progression
Abstract
:1. Introduction
2. A Review of Autophagy
3. Autophagy in Gastric Cancer
3.1. Regulation of Autophagy by MicroRNAs (miRNAs)
3.2. Regulation of Autophagy by miRNAs as Tumor Suppressor Genes
3.3. Regulation of Autophagy by miRNAs as Oncogenes
3.4. Regulation of Autophagy by Long Non-Coding RNAs (lncRNAs)
3.5. Regulation of Autophagy by PI3K/AKT/mTOR Signaling Pathway
3.6. Regulation of Autophagy by AMPK Signaling Pathway
3.7. Autophagy and Helicobacter pyloriin Gastric Cancer
3.8. Atgs in Tumorigenesis of Gastric Cancer
4. Targeted Autophagy as Putative Therapeutic Approach
4.1. Autophagy Enhancer Agents
4.2. Autophagy Inhibitors
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ATGs | Autophagy-related genes |
CAB | calcium-binding protein |
CagA | cytotoxin-associated gene A |
ceRNA | competing for endogenous RNA |
CDH1 | Cadherin 1 |
CMA | Chaperon-mediated autophagy |
CTNNA1 | Catenin Alpha 1 |
CQ | Chloroquine |
DCMI | desmethylclomipramine |
DDP | diamminedichloroplatinum |
EAC | Esophageal adenocarcinoma |
EBV | Epstein–Barr virus |
EMT | epithelial-to-mesenchymal transition |
FAP | Familial Adenomatous Polyposis |
GAPPS | stomach syndrome |
GC | Gastric cancer |
GIM | gastric intestinal metaplasia |
GSTM1 | Glutathione S-Transferase Mu 1 |
HCQ | hydroxychloroquine |
HDGC | Diffuse Gastric Cancer |
HNPCC | Hereditary Non-Polyposis Colorectal Cancer |
HOTTIP | HOXA distal transcript antisense RNA |
H. pylori | Helicobacter pylori |
IL | interleukin |
KFERQ | consensus pentapeptide of cytosolic chaperone hsc70 |
LAMP-2A | lysosomal membrane protein 2A |
lncRNAs | Long Non-Coding RNAs |
MALAT1 | metastasis-associated lung adenocarcinoma transcript 1 |
MEFs | Mouse Embryonic Fibroblasts |
MSI | microsatellite instability |
mTOR | mammalian target of rapamycin |
PE | phosphatidylethanolamine |
PGE2prostaglandin | E2 |
PPIs | Proton-pump inhibitors |
UVRAG | Ultraviolet radiation resistance-associated gene |
VacA | vacuolating cytotoxin |
VEGF | Vascular endothelial growth factor |
5-FU | 5-fluorouracil |
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
- Balakrishnan, M.; George, R.; Sharma, A.; Graham, D.Y. Changing Trends in Stomach Cancer ThroughouttheWorld. Curr. Gastroenterol. Rep. 2017, 19, 36. [Google Scholar] [CrossRef]
- Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021, 149, 778–789. [Google Scholar] [CrossRef] [PubMed]
- Bray, F.; Ferlay, J.; Laversanne, M.; Brewster, D.; Mbalawa, C.G.; Kohler, B.; Piñeros, M.; Steliarova-Foucher, E.; Swaminathan, R.; Antoni, S.; et al. Cancer incidence in five continents: Inclusion criteria, highlights from Volume X and the global status of cancer registration. Int. J. Cancer 2015, 137, 2060–2071. [Google Scholar] [CrossRef]
- Forman, D.; Burley, V.J. Gastric cancer: Global pattern of the disease and an overview of environmental risk factors. Best Pract. Res. Clin. Gastroenterol. 2006, 20, 633–649. [Google Scholar] [CrossRef] [PubMed]
- Camargo, M.C.; Goto, Y.; Zabaleta, J.; Morgan, D.R.; Correa, P.; Rabkin, C.S. Sex hormones, hormonal interventions, and gastric cancer risk: A meta-analysis. Cancer Epidemiol. Biomark. Prev. 2012, 21, 20–38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Anderson, W.F.; Camargo, M.C.; Fraumeni, J.F., Jr.; Correa, P.; Rosenberg, P.S.; Rabkin, C.S. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 2010, 303, 1723–1728. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR). Diet, Nutrition, Physical Activity and Stomach Cancer 2016; Continuous Update Project Report; World Cancer Research Fund International: London, UK, 2008. [Google Scholar]
- IARC. Schistosomes, Liver Flukes and Helicobacter Pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; IARC Monogr Eval Carcinog Risks Hum: Lyon, France, 1994; Volume 61, pp. 1–241. [Google Scholar]
- Bouvard, V.; Loomis, D.; Guyton, K.Z.; Grosse, Y.; Ghissassi, F.E.; Benbrahim-Tallaa, L.; Guha, N.; Mattock, H.; Straif, K. International Agency for Research on Cancer Monograph Working Group Carcinogenicity of Consumption of Red and Processed Meat. Lancet Oncol. 2015, 16, 1599–1600. [Google Scholar] [CrossRef] [Green Version]
- Gupta, S.; Tao, L.; Murphy, J.D.; Camargo, M.C.; Oren, E.; Valasek, M.A.; Gomez, S.L.; Martinez, M.E. Race/ethnicity-, socioeconomic status-, and anatomic subsite-specific risks for gastric cancer. Gastroenterology 2019, 156, 59–62.e4. [Google Scholar] [CrossRef]
- Molloy, R.M.; Sonnenberg, A. Relation between gastric cancer and previous peptic ulcer disease. Gut 1997, 40, 247–252. [Google Scholar] [CrossRef] [Green Version]
- Derakhshan, M.H.; Malekzadeh, R.; Watabe, H.; Yazdanbod, A.; Fyfe, V.; Kazemi, A.; Rakhshani, N.; Didevar, R.; Sotoudeh, M.; Zolfeghari, A.A.; et al. Combination of gastric atrophy, reflux symptoms and histological subtype indicates two distinct aetiologies of gastric cardia cancer. Gut 2008, 57, 298–305. [Google Scholar] [CrossRef] [Green Version]
- Gupta, S.; Li, D.; El Serag, H.B.; Davitkov, P.; Altayar, O.; Sultan, S.; Falck-Ytter, Y.; Mustafa, R.A. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology 2020, 158, 693–702. [Google Scholar] [CrossRef] [Green Version]
- Take, S.; Mizuno, M.; Ishiki, K.; Nagahara, Y.; Yoshida, T.; Yokota, K.; Oguma, K.; Okada, H.; Shiratori, Y. The effect of eradicating Helicobacter pylori on the development of gastric cancer in patients with peptic ulcer disease. Am. J. Gastroenterol. 2005, 100, 1037–1042. [Google Scholar] [CrossRef] [PubMed]
- Karimi, P.; Islami, F.; Anandasabapathy, S.; Freedman, N.D.; Kamangar, F. Gastric cancer: Descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol. Biomark. Prev. 2014, 23, 700–713. [Google Scholar] [CrossRef] [Green Version]
- Boysen, T.; Mohammadi, M.; Melbye, M.; Hamilton-Dutoit, S.; Vainer, B.; Hansen, A.V.; Wohlfahrt, J.; Friborg, J. EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma. Br. J. Cancer 2009, 101, 530–533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Camargo, M.C.; Figueiredo, C.; Machado, J.C. Review: Gastric Malignancies: Basic Aspects. Helicobacter 2019, 24, e12642. [Google Scholar] [CrossRef] [PubMed]
- Huang, S.-C.; Ng, K.-F.; Yeh, T.-S.; Cheng, C.-T.; Lin, J.-S.; Liu, Y.-J.; Chuang, H.-C.; Chen, T.-C. Subtraction of Epstein–Barr Virus and Microsatellite Instability Genotypes from the Lauren Histotypes: Combined Molecular and Histologic Subtyping with Clinicopathological and Prognostic Significance Validated in a Cohort of 1248 Cases. Int. J. Cancer 2019, 145, 3218–3230. [Google Scholar] [CrossRef]
- Takeno, S.; Hashimoto, T.; Maki, K.; Shibata, R.; Shiwaku, H.; Yamana, I.; Yamashita, R.; Yamashita, Y. Gastric cancer arising from the remnant stomach after distal gastrectomy: A review. World J. Gastroenterol. 2014, 20, 13734–13740. [Google Scholar] [CrossRef]
- Lagergren, J.; Lindam, A.; Mason, R.M. Gastric stump cancer after distal gastrectomy for benign gastric ulcer in a population-based study. Int. J. Cancer 2012, 131, 1048–1052. [Google Scholar] [CrossRef] [Green Version]
- Xu, J.L.; Yuan, L.; Tang, Y.C.; Xu, Z.Y.; Xu, H.D.; Cheng, X.D.; Qin, J.J. The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe? Front. Cell Dev. Biol. 2020, 8, 621428. [Google Scholar] [CrossRef]
- Correa, P.; Piazuelo, M.B. The Gastric Precancerous Cascade. J. Dig. Dis. 2012, 13, 2–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Correa, P. Gastric cancer: Overview. Gastroenterol. Clin. N. Am. 2013, 42, 211–217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lauren, P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma.An. attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand. 1965, 64, 31–49. [Google Scholar] [CrossRef]
- Muro, K.; Van Cutsem, E.; Narita, Y.; Pentheroudakis, G.; Baba, E.; Li, J.; Ryu, M.H.; Zamaniah, W.I.W.; Yong, W.P.; Yeh, K.H.; et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: A JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann. Oncol. 2019, 30, 19–33. [Google Scholar] [CrossRef]
- Joshi, S.S.; Badgwell, B.D. Current treatment and recent progress in gastric cancer. CA Cancer J. Clin. 2021, 71, 264–279. [Google Scholar] [CrossRef]
- Oliveira, C.; Seruca, R.; Carneiro, F. Genetics, Pathology, and Clinics of Familial Gastric Cancer. Int. J. Surg. Pathol. 2016, 14, 21–33. [Google Scholar] [CrossRef]
- Rawla, P.; Barsouk, A. Epidemiology of gastric cancer: Global trends, risk factors and prevention. Gastroenterol. Rev. 2019, 14, 26–38. [Google Scholar] [CrossRef] [PubMed]
- Seeneevassen, L.; Bessède, E.; Mégraud, F.; Lehours, P.; Dubus, P.; Varon, C. Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies. Int. J. Mol. Sci. 2021, 22, 3418. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Liang, Y.; Ma, M.H.; Wu, K.Z.; Zhang, C.D.; Dai, D.Q. Downregulation of microRNA-376a in Gastric Cancer and Association with Poor Prognosis. Cell. Physiol. Biochem. 2018, 51, 2010–2018. [Google Scholar] [CrossRef]
- Piletič, K.; Kunej, T. MicroRNA epigenetic signatures in human disease. Arch. Toxicol. 2016, 90, 2405–2419. [Google Scholar] [CrossRef]
- Koustas, E.; Karamouzis, M.V.; Mihailidou, C.; Schizas, D.; Papavassiliou, A.G. Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer. Cancer Lett. 2017, 396, 94–102. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Klionsky, D.J. Autophagy and disease: Unanswered questions. Cell Death Differ. 2020, 27, 858–871. [Google Scholar] [CrossRef]
- Koustas, E.; Sarantis, P.; Kyriakopoulou, G.; Papavassiliou, A.G.; Karamouzis, M.V. The Interplay of Autophagy and Tumor Microenvironment in Colorectal Cancer-Ways of Enhancing Immunotherapy Action. Cancers 2019, 11, 533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Andrade-Tomaz, M.; de Souza, I.; Rocha, C.R.R.; Gomes, L.R. The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer. Cells 2020, 9, 2140. [Google Scholar] [CrossRef]
- Levy, J.M.M.; Towers, C.G.; Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 2017, 17, 528–542. [Google Scholar] [CrossRef]
- Wang, X.; Wu, W.K.K.; Gao, J.; Li, Z.; Dong, B.; Lin, X.; Li, Y.; Li, Y.; Gong, J.; Qi, C.; et al. Autophagy inhibition enhances PD-L1 expression in gastric cancer. J. Exp. Clin. Cancer Res. 2019, 38, 140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42. [Google Scholar] [CrossRef] [Green Version]
- White, E.; Mehnert, J.M.; Chan, C.S. Autophagy, Metabolism, and Cancer. Clin. Cancer Res. 2015, 21, 5037–5046. [Google Scholar] [CrossRef] [Green Version]
- Lim, S.M.; Mohamad Hanif, E.A.; Chin, S.F. Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect. Cell Biosci. 2021, 11, 56. [Google Scholar] [CrossRef]
- Hwang, J.; Min, B.H.; Jang, J.; Kang, S.Y.; Bae, H.; Jang, S.S.; Kim, J.I.; Kim, K.M. MicroRNA Expression Profiles in Gastric Carcinogenesis. Sci. Rep. 2018, 8, 14393. [Google Scholar] [CrossRef] [PubMed]
- Akkoc, Y.; Gozuacik, D. MicroRNAs as major regulators of the autophagy pathway. Biochim. Biophys. Acta Mol. Cell Res. 2020, 1867, 118662. [Google Scholar] [CrossRef]
- Xiu, T.; Guo, Q.; Jing, F.B. Facing Cell Autophagy in Gastric Cancer—What Do We Know so Far? Int. J. Gen. Med. 2021, 14, 1647–1659. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Wong, C.C.; Zhang, X.; Kang, W.; Nakatsu, G.; Zhao, Q.; Chen, H.; Go, M.Y.Y.; Chiu, P.W.Y.; Wang, X.; et al. CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1α axis to inhibit gastric tumorigenesis. Oncogene 2018, 37, 6383–6398. [Google Scholar] [CrossRef]
- Xu, Z.; Li, Z.; Wang, W.; Xia, Y. MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy. Cancer Lett. 2019, 449, 226–236. [Google Scholar] [CrossRef] [PubMed]
- Gu, Y.; Fei, Z.; Zhu, R. MiR-21 modulates cisplatin resistance of gastric cancer cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Anti-Cancer Drugs 2020, 31, 385–393. [Google Scholar] [CrossRef]
- Tian, L.; Zhao, Z.; Xie, L.; Zhu, J. MiR-361-5p suppresses chemoresistance of gastric cancer cells by targeting FOXM1 via the PI3K/Akt/mTOR pathway. Oncotarget 2018, 9, 4886–4896. [Google Scholar] [CrossRef] [Green Version]
- Yuan, Y.; Zhang, Y.; Han, L.; Sun, S.; Shu, Y. miR-183 inhibits autophagy and apoptosis in gastric cancer cells by targeting ultraviolet radiation resistance-associated gene. Int. J. Mol. Med. 2018, 42, 3562–3570. [Google Scholar] [CrossRef] [Green Version]
- Cao, L.L.; Xie, J.W.; Lin, Y.; Zheng, C.H.; Li, P.; Wang, J.B.; Lin, J.X.; Lu, J.; Chen, Q.Y.; Huang, C.M. miR-183 inhibits invasion of gastric cancer by targeting Ezrin. Int. J. Clin. Exp. Pathol. 2014, 7, 5582–5594. [Google Scholar]
- Yuan, L.; Xu, Z.Y.; Ruan, S.M.; Mo, S.; Qin, J.J.; Cheng, X.D. Long non-coding RNAs towards precision medicine in gastric cancer: Early diagnosis, treatment, and drug resistance. Mol. Cancer 2020, 19, 96. [Google Scholar] [CrossRef] [PubMed]
- Fu, S.; Wang, Y.; Li, H.; Chen, L.; Liu, Q. Regulatory Networks of LncRNA MALAT-1 in Cancer. Cancer Manag. Res. 2020, 12, 10181–10198. [Google Scholar] [CrossRef]
- Xin, L.; Zhou, Q.; Yuan, Y.W.; Zhou, L.Q.; Liu, L.; Li, S.H.; Liu, C. METase/lncRNA HULC/FoxM1 reduced cisplatin resistance in gastric cancer by suppressing autophagy. J. Cancer Res. Clin. Oncol. 2019, 145, 2507–2517. [Google Scholar] [CrossRef] [PubMed]
- Zhao, R.; Zhang, X.; Zhang, Y.; Zhang, Y.; Yang, Y.; Sun, Y.; Zheng, X.; Qu, A.; Umwali, Y.; Zhang, Y. HOTTIP predicts poor survival in gastric cancer patients and contributes to cisplatin resistance by sponging miR-216a-5p. Front. Cell Dev. Biol. 2020, 8, 348. [Google Scholar] [CrossRef]
- Hu, Y.; Yu, Y.; You, S.; Li, K.; Tong, X.; Chen, S.; Chen, E.; Lin, X.; Chen, Y. Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer. Mol. Cancer 2017, 16, 174. [Google Scholar] [CrossRef] [Green Version]
- Xi, Z.; Si, J.; Nan, J. LncRNA MALAT1 potentiates autophagy-associated cisplatin resistance by regulating the microRNA-30b/autophagy-related gene 5 axis in gastric cancer. Int. J. Oncol. 2019, 54, 239–248. [Google Scholar] [CrossRef] [Green Version]
- Chen, J.F.; Wu, P.; Xia, R.; Yang, J.; Huo, X.Y.; Gu, D.Y.; Tang, C.J.; De, W.; Yang, F. STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy. Mol. Cancer 2018, 17, 6. [Google Scholar] [CrossRef] [Green Version]
- Li, X.; He, S.; Ma, B. Autophagy and autophagy-related proteins in cancer. Mol. Cancer 2020, 19, 12. [Google Scholar] [CrossRef]
- Zheng, W.; Wu, C.; Wu, X.; Cai, Y.; Liu, B.; Wang, C. Genetic variants of autophagy-related genes in the PI3K/Akt/mTOR pathway and risk of gastric cancer in the Chinese population. Gene 2021, 769, 145190. [Google Scholar] [CrossRef] [PubMed]
- Liu, R.; Chen, Y.; Liu, G.; Li, C.; Song, Y.; Cao, Z.; Li, W.; Hu, J.; Lu, C.; Liu, Y. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020, 11, 797. [Google Scholar] [CrossRef]
- Saxton, R.A.; Sabatini, D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017, 168, 960–976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guo, F.; Jiao, D.; Sui, G.Q.; Sun, L.N.; Gao, Y.J.; Fu, Q.F.; Jin, C.X. Anticancer effect of YWHAZ silencing via inducing apoptosis and autophagy in gastric cancer cells. Neoplasma 2018, 65, 693–700. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Liu, S.; Feng, Q.; Huang, X.; Wang, X.; Peng, Y.; Zhao, Z.; Liu, Z. Perilaldehyde activates AMP-activated protein kinase to suppress the growth of gastric cancer via induction of autophagy. J. Cell Biochem. 2018, 120, 1716–1725. [Google Scholar] [CrossRef]
- Vara-Ciruelos, D.; Russell, F.M.; Hardie, D.G. The strange case of AMPK and cancer: Dr Jekyll or Mr Hyde? Open Biol. 2019, 9, 190099. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Piscione, M.; Mazzone, M.; Di Marcantonio, M.C.; Muraro, R.; Mincione, G. Eradication of Helicobacter pylori and Gastric Cancer: A Controversial Relationship. Front. Microbiol. 2021, 12, 630852. [Google Scholar] [CrossRef] [PubMed]
- Ferreira, R.M.; Machado, J.C.; Figueiredo, C. Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma. Best Pract. Res. Clin. Gastroenterol. 2014, 28, 1003–1015. [Google Scholar] [CrossRef] [PubMed]
- Qian, H.R.; Yang, Y. Functional role of autophagy in gastric cancer. Oncotarget 2016, 7, 17641–17651. [Google Scholar] [CrossRef] [Green Version]
- Zhang, F.; Chen, C.; Hu, J.; Su, R.; Zhang, J.; Han, Z.; Chen, H.; Li, Y. Molecular mechanism of Helicobacter pylori-induced autophagy in gastric cancer. Oncol. Lett. 2019, 18, 6221–6227. [Google Scholar] [CrossRef] [Green Version]
- Castrejon-Jimenez, N.S.; Leyva-Paredes, K.; Hernandez-Gonzalez, J.C.; Luna-Herrera, J.; Garcia-Perez, B.E. The role of autophagy in bacterial infections. Biosci. Trends. 2015, 9, 149–159. [Google Scholar] [CrossRef] [Green Version]
- Raju, D.; Hussey, S.; Ang, M.; Terebiznik, M.R.; Sibony, M.; Galindo-Mata, E.; Gupta, V.; Blanke, S.R.; Delgado, A.; Romero-Gallo, J.; et al. Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology 2012, 142, 1160–1171. [Google Scholar] [CrossRef] [Green Version]
- Terebiznik, M.R.; Raju, D.; Vazquez, C.L.; Torbricki, K.; Kulkarni, R.; Blanke, S.R.; Yoshimori, T.; Colombo, M.I.; Jones, N.L. Effect of Helicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy 2009, 5, 370–379. [Google Scholar] [CrossRef] [Green Version]
- Tang, B.; Li, N.; Gu, J.; Zhuang, Y.; Li, Q.; Wang, H.G.; Fang, Y.; Yu, B.; Zhang, J.Y.; Xie, Q.H.; et al. Compromised autophagy by MIR30B benefits the intracellular survival of Helicobacter pylori. Autophagy 2012, 8, 1045–1057. [Google Scholar] [CrossRef] [Green Version]
- Kim, J.S.; Bae, G.E.; Kim, K.H.; Lee, S.I.; Chung, C.; Lee, D.; Lee, T.H.; Kwon, I.S.; Yeo, M.K. Prognostic Significance of LC3B and p62/SQSTM1 Expression in Gastric Adenocarcinoma. Anticancer Res. 2019, 39, 6711–6722. [Google Scholar] [CrossRef] [Green Version]
- Anding, A.L.; Baehrecke, E.H. Cleaning house: Selective autophagy of organelles. Dev. Cell. 2017, 41, 10–22. [Google Scholar] [CrossRef] [Green Version]
- Lee, J.W.; Jeong, E.G.; Lee, S.H.; Yoo, N.J. Somatic mutations of BECN1, an autophagy-related gene, in human cancers. APMIS 2007, 115, 750–756. [Google Scholar] [CrossRef]
- Qu, L.; Yao, H.L.; Ma, H.L.; Chen, H.L.; Zhang, Z.; Xie, J. Prognostic significance ofautophagy-related proteins expression in resected human gastric adenocarcinoma. J.Huazhong Univ. Sci. Technol. Med. Sci. 2017, 37, 37–43. [Google Scholar] [CrossRef] [PubMed]
- Yu, S.; Li, G.; Wang, Z.; Wang, Z.; Chen, C.; Cai, S.; He, Y. Low expression ofMAP1LC3B, associated with low Beclin-1, predicts lymph node metastasis andpoor prognosis of gastric cancer. Tumour Biol. 2016, 37, 15007–15017. [Google Scholar] [CrossRef] [PubMed]
- An, C.H.; Kim, M.S.; Yoo, N.J.; Park, S.W.; Lee, S.H. Mutational and expressional analyses of ATG5, an autophagy-related gene, in gastrointestinal cancers. Pathol. Res. Pract. 2011, 207, 433–437. [Google Scholar] [CrossRef]
- Vigen, R.A.; Kodama, Y.; Viset, T.; Fossmark, R.; Waldum, H.; Kidd, M.; Wang, T.C.; Modlin, I.M.; Chen, D.; Zhao, C.M. Immunohistochemical evidence for an impairment of autophagy in tumorigenesis of gastric carcinoids and adenocarcinomas in rodent models and patients. Histol. Histopathol. 2013, 28, 531–542. [Google Scholar]
- Kim, M.S.; Jeong, E.G.; Ahn, C.H.; Kim, S.S.; Lee, S.H.; Yoo, N.J. Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. Hum. Pathol. 2008, 39, 1059–1063. [Google Scholar] [CrossRef]
- Cao, Y.; Luo, Y.; Zou, J.; Ouyang, J.; Cai, Z.; Zeng, X.; Ling, H.; Zeng, T. Autophagy and its role in gastric cancer. Clin. Chim. Acta 2019, 489, 10–20. [Google Scholar] [CrossRef]
- Maes, H.; Kuchnio, A.; Peric, A.; Moens, S.; Nys, K.; De Bock, K.; Quaegebeur, A.; Schoors, S.; Georgiadou, M.; Wouters, J.; et al. Tumor vessel normalizationby chloroquine independent of autophagy. Cancer Cell 2014, 26, 190–206. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dong, X.; Wang, Y.; Zhou, Y.; Wen, J.; Wang, S.; Shen, L. Aquaporin 3 facilitates chemoresistance in gastric cancer cells to cisplatin via autophagy. Cell Death Discov. 2016, 2, 16087. [Google Scholar] [CrossRef]
- Onorati, A.V.; Dyczynski, M.; Ojha, R.; Amaravadi, R.K. Targeting autophagy in cancer. Cancer 2018, 124, 3307–3318. [Google Scholar] [CrossRef] [Green Version]
- Koustas, E.; Trifylli, E.M.; Sarantis, P.; Papavassiliou, A.G.; Karamouzis, M.V. Role of autophagy in cholangiocarcinoma: An autophagy-based treatment strategy. World J. Gastrointest. Oncol. 2021, 13, 1229–1243. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Li, D.; Li, X.; Ou, X.; Liu, S.; Zhang, Y.; Ding, J.; Xie, B. Mammalian target of Rapamycin inhibitor RAD001 sensitizes endometrial cancer cells to paclitaxel-induced apoptosis via the induction of autophagy. Oncol. Lett. 2016, 12, 5029–5035. [Google Scholar] [CrossRef]
- Byun, S.; Lee, E.; Lee, K.W. Therapeutic Implications of Autophagy Inducers in Immunological Disorders, Infection, and Cancer. Int. J. Mol. Sci. 2017, 18, 1959. [Google Scholar] [CrossRef] [PubMed]
- Liu, S.; Yue, C.; Chen, H.; Chen, Y.; Li, G. Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer. Onco Targets Ther. 2020, 13, 4445–4455. [Google Scholar] [CrossRef]
- Bhattacharya, U.; Neizer-Ashun, F.; Mukherjee, P.; Bhattacharya, R. When the chains do not break: The role of USP10 in physiology and pathology. Cell Death Dis. 2020, 11, 1033. [Google Scholar] [CrossRef]
- Yeo, S.K.; Paul, R.; Haas, M.; Wang, C.; Guan, J.L. Improved efficacy of mitochondrial disrupting agents upon inhibition of autophagy in a mouse model of BRCA1-deficient breast cancer. Autophagy 2018, 14, 1214–1225. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abrahamsen, H.; Stenmark, H.; Platta, H.W. Ubiquitination and phosphorylation of Beclin 1 and its binding partners: Tuning class III phosphatidylinositol 3-kinase activity and tumor suppression. FEBS Lett. 2012, 586, 1584–1591. [Google Scholar] [CrossRef]
- Lin, S.Y.; Hsieh, S.Y.; Fan, Y.T.; Wei, W.C.; Hsiao, P.W.; Tsai, D.H.; Wu, T.S.; Yang, N.S. Necroptosis promotes autophagy-dependent upregulation of DAMP and results in immunosurveillance. Autophagy 2018, 14, 778–795. [Google Scholar] [CrossRef] [Green Version]
- Yu, L.; Wu, W.K.; Gu, C.; Zhong, D.; Zhao, X.; Kong, Y.; Lin, Q.; Chan, M.T.; Zhou, Z.; Liu, S. Obatoclax impairs lysosomal function to block autophagy in cisplatin-sensitive and -resistant esophageal cancer cells. Oncotarget 2016, 7, 14693. [Google Scholar] [CrossRef]
- Siasos, G.; Tousoulis, D.; Oikonomou, E.; Zaromitidou, M.; Verveniotis, A.; Plastiras, A.; Kioufis, S.; Maniatis, K.; Miliou, A.; Siasou, Z.; et al. Effects of Ω-3 fatty acids on endothelial function, arterial wall properties, inflammatory and fibrinolytic status in smokers: A cross over study. Int. J. Cardiol. 2013, 166, 340–346. [Google Scholar] [CrossRef]
- Mulcahy Levy, J.M.; Thorburn, A. Autophagy in cancer: Moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ. 2020, 27, 843–857. [Google Scholar] [CrossRef]
- Koustas, E.; Sarantis, P.; Karamouzis, M.V.; Vielh, P.; Theocharis, S. The Controversial Role of Autophagy in Ewing Sarcoma Pathogenesis-Current Treatment Options. Biomolecules 2021, 11, 355. [Google Scholar] [CrossRef] [PubMed]
- Koustas, E.; Papavassiliou, A.G.; Karamouzis, M.V. The role of autophagy in the treatment of BRAF mutant colorectal carcinomas differs based on microsatellite instability status. PLoS ONE 2018, 13, e0207227. [Google Scholar] [CrossRef] [Green Version]
- Rosenfeld, M.R.; Ye, X.; Supko, J.G.; Desideri, S.; Grossman, S.A.; Brem, S.; Mikkelson, T.; Wang, D.; Chang, Y.C.; Hu, J.; et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 2014, 10, 1359–1368. [Google Scholar] [CrossRef]
- Boone, B.A.; Bahary, N.; Zureikat, A.H.; Moser, A.J.; Normolle, D.P.; Wu, W.C.; Singhi, A.D.; Bao, P.; Bartlett, D.L.; Liotta, L.A.; et al. Safety and Biologic Response of Preoperative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Ann. Surg. Oncol. 2015, 22, 4402–4410. [Google Scholar] [CrossRef] [PubMed]
- Mukhopadhyay, S.; Mahapatra, K.K.; Praharaj, P.P.; Patil, S.; Bhutia, S.K. Recent progress of autophagy signaling in tumor microenvironment and its targeting for possible cancer therapeutics. Semin. Cancer Biol. 2021. [Google Scholar] [CrossRef]
- Ahwazi, D.; Neopane, K.; Markby, G.R.; Kopietz, F.; Ovens, A.J.; Dall, M.; Hassing, A.S.; Gräsle, P.; Alshuweishi, Y.; Treebak, J.T.; et al. Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965. Biochem. J. 2021, 478, 2977–2997. [Google Scholar] [CrossRef] [PubMed]
- Kocaturk, N.M.; Akkoc, Y.; Kig, C.; Bayraktar, O.; Gozuacik, D.; Kutlu, O. Autophagy as a molecular target for cancer treatment. Eur. J. Pharm. Sci. 2019, 134, 116–137. [Google Scholar] [CrossRef]
- Vakifahmetoglu-Norberg, H.; Xia, H.G.; Yuan, J. Pharmacologic agents targeting autophagy. J. Clin. Investig. 2015, 125, 5–13. [Google Scholar] [CrossRef] [Green Version]
- Rossi, M.; Munarriz, E.R.; Bartesaghi, S.; Milanese, M.; Dinsdale, D.; Guerra-Martin, M.A.; Bampton, E.T.; Glynn, P.; Bonanno, G.; Knight, R.A.; et al. Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux. J. Cell Sci. 2009, 122, 3330–3339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Koustas, E.; Sarantis, P.; Papavassiliou, A.G.; Karamouzis, M.V. The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors. Biomolecules 2020, 10, 666. [Google Scholar] [CrossRef] [PubMed]
- Sun, S.Y. Enhancing perifosine’s anticancer efficacy by preventing autophagy. Autophagy 2010, 6, 184–185. [Google Scholar] [CrossRef] [Green Version]
- Rangwala, R.; Chang, Y.Y.C.; Hu, J.; Algazy, K.; Evans, T.; Fecher, L.; Schuchter, L.; Torigian, D.A.; Panosian, J.; Troxel, A.; et al. Combined mTOR and autophagy inhibition Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 2014, 10, 1391–1402. [Google Scholar] [CrossRef]
- Zang, Y.; Thomas, S.M.; Chan, E.T.; Kirk, C.J.; Freilino, M.L.; DeLancey, H.M.; Grandis, J.R.; Li, C.Y.; Johnson, D.E. The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4. Autophagy 2012, 8, 1873–1874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chang, H.; Zou, Z. Targeting autophagy to overcome drug resistance: Further developments. J. Hematol. Oncol. 2020, 13, 159. [Google Scholar] [CrossRef] [PubMed]
ATGs | Human Orthologue | Autophagy Step | Molecular Function |
---|---|---|---|
Atg1 | ULK1/2 | Induction | Kinase |
Atg2 | ATG2A, ATG2B | Nucleation | Protein binding |
Atg3 | ATG3 | Elongation | Ubiquitin-like ligase |
Atg4a | ATG4A, ATG4B | Elongation | Cysteine-type endopeptidase |
Atg4b | ATG4C | Elongation | Cysteine-type endopeptidase |
Atg5 | ATG5 | Maturation | Ubiquitin-like ligase |
Atg6 | BECN1 | Nucleation | Kinase |
Atg7 | ATG7 | Elongation | Ubiquitin-activating enzyme |
Atg8a | GABARAP | Elongation | Ubiquitin-like |
Atg8b | MAP1LC3C, MAP1LC3B2 | Elongation | Ubiquitin-like modifying enzyme |
Atg9 | ATG9A, ATG9B | Nucleation | Protein binding |
Atg10 | ATG10 | Maturation | Ubiquitin-like ligase |
Atg12 | ATG12 | Maturation | Ubiquitin-like |
Atg13 | ATG13 | Induction | Protein kinase binding |
Atg14 | ATG14 | Nucleation | Kinase |
Atg16 | ATG16L1, ATG16L2 | Maturation | Ubiquitin-like ligase |
Atg17 | RB1CC1 | Induction | Protein kinase binding |
Atg18a | WIPI2 | Nucleation | PIP2 binding |
Atg101 | ATG101 | Induction | Protein binding |
Agents | Mechanism of Action | Target |
---|---|---|
Rapamycin | mTORC1 inhibitor | Formation of Autophagosome |
Deforolimus | mTORC1 inhibitor | Formation of Autophagosome |
Temsirolimus | mTORC1 inhibitor | Formation of Autophagosome |
Everolimus | mTORC1 inhibitor | Formation of Autophagosome |
GDC-0941 | PI3K Class I inhibitor | Formation of Autophagosome |
GDC-0980 | PI3K and mTORC1 inhibitor | Formation of Autophagosome |
Tat–Beclin-1 peptide | Releases Beclin-1 into cytoplasm | Formation of Autophagosome |
Perifosine | AKT inhibitior | Formation of Autophagosome |
Metformin | AMPK activator | Formation of Autophagosome |
fluspirilene | Antagonists of L-type Ca2+ channels | Lysosome |
cepharanthine | Natural alkaloid | Autophagic flux |
isoliensinine | Natural alkaloid | Autophagic flux |
Agents | Mechanism of Action | Target |
---|---|---|
Chloroquine (CQ) | Neutralizes the acidic pH of intracellular vesicles | Lysosome |
Hydroxy-chloroquine (HCQ) | CQ derivative | Lysosome |
Bafilomycin A1 | Inhibition of lysosomal acidification | Lysosome |
Azithromycin | Inhibition of lysosomal acidification | Lysosome |
Concanamycin A | Inhibition of lysosomal acidification | Lysosome |
3-Methyladenine (3-MA) | PI3K- Class III inhibitor | Formation of Autophagosome |
Wortmannin | PI3K- Class III inhibitor | Formation of Autophagosome |
LY294002 | PI3K- Class III inhibitor | Formation of Autophagosome |
LY3023414 | PI3K- Class III inhibitor | Formation of Autophagosome |
SAR405 | Vps18 and Vps34) inhibitor | Formation of Autophagosome |
SB203580 | Inhibit trafficking of Atg9 | Formation of Autophagosome |
Paclitaxel | Microtubule stabilizer inhbits phosphorylation of VPS34 | Formation of Autophagosome |
SAHA | Inhibit fusion of autophagosome and lysosome | Formation of Autophagosome |
Sputin-1 | (USP10) and (USP13) inhibitor | Formation of Autophagosome |
NSC185058 | ATG4 inhibitor | Formation of Autophagosome |
Verteporfin | Alter lysosomes accedification | Formation of Autophagosome |
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Koustas, E.; Trifylli, E.-M.; Sarantis, P.; Kontolatis, N.I.; Damaskos, C.; Garmpis, N.; Vallilas, C.; Garmpi, A.; Papavassiliou, A.G.; Karamouzis, M.V. The Implication of Autophagy in Gastric Cancer Progression. Life 2021, 11, 1304. https://doi.org/10.3390/life11121304
Koustas E, Trifylli E-M, Sarantis P, Kontolatis NI, Damaskos C, Garmpis N, Vallilas C, Garmpi A, Papavassiliou AG, Karamouzis MV. The Implication of Autophagy in Gastric Cancer Progression. Life. 2021; 11(12):1304. https://doi.org/10.3390/life11121304
Chicago/Turabian StyleKoustas, Evangelos, Eleni-Myrto Trifylli, Panagiotis Sarantis, Nikolaos I. Kontolatis, Christos Damaskos, Nikolaos Garmpis, Christos Vallilas, Anna Garmpi, Athanasios G. Papavassiliou, and Michalis V. Karamouzis. 2021. "The Implication of Autophagy in Gastric Cancer Progression" Life 11, no. 12: 1304. https://doi.org/10.3390/life11121304