CISD2 enhances the chemosensitivity of gastric cancer through the enhancement of 5‐FU‐induced apoptosis and the inhibition of autophagy by AKT/mTOR pathway. (31st August 2017)

• Record Type: Journal Article
• Authors: Sun, Yi; Jiang, Yingming; Huang, Jintuan; Chen, Hao; Liao, Yi; Yang, Zuli
• Is Part Of: Cancer medicine. Volume 6:Number 10(2017:Oct.)
• Page Start: 2331
• Page End: 2346
• Publication Date: 2017-08-31
• Subjects: 5‐FU -- apoptosis -- autophagy -- chemotherapeutic sensitivity -- cisd2 -- gastric cancer; 616.994005
• DOI: 10.1002/cam4.1169
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Gastric cancer (GC) is a prevalent upper gastrointestinal tumor characterized by high morbidity and mortality due to imperfect screening systems and the rapid development of resistance to 5‐fluorouracil (5‐FU). CDGSH iron sulfur domain 2 (CISD2) has been recently regarded as a candidate oncogene in several types of tumors. It is, therefore, necessary to investigate its biological function and clinical significance in gastric cancer. In this study, the down‐regulated expression level of CISD2 in GC compared with adjacent normal tissues was evaluated by quantitative RT‐PCR and Western blotting. An immunohistochemical analysis indicated that CISD2 expression in GC was significantly correlated with age ( P = 0.002), Lauren's classification ( P = 0.001), and differentiation ( P = 0.049). Two cell lines, MKN1 and BGC823, were used to analyze the role of CISD2 in gastric carcinogenesis and response to 5‐FU through CCK‐8 assays, the RT‐CES system, Transwell assays, flow cytometry, and confocal fluorescence microscopy. The overexpression of CISD2 resulted in reduced cellular growth and proliferation, inhibition of metastatic ability, and increased apoptosis. 5‐FU treatment increased endogenous as well as exogenous overexpression of CISD2 in GC cells. Further investigation revealed that CISD2 enhanced sensitivity to 5‐FU via an increase in apoptosis and inhibition of protective autophagy through the activation of the AKT/mTOR pathway. In conclusion, CISD2 is down‐regulated in gastric cancer, and its effects on the inhibition of cellular proliferation, metastatic ability, and increased chemotherapy sensitivity are mediated by antagonism to 5‐FU‐induced autophagy through the AKT/mTOR pathway. Abstract : This study showed that CISD2 is down‐regulated in gastric cancer tissues, and significantly correlated with age, Lauren's classification, and differentiation. The inhibitory effect of CISD2 on gastric cancer cell proliferation, migration invasion, and increase chemotherapy sensitivity are mediated by enhancing 5‐FU‐induced apoptosis and inhibiting autophagy through AKT/mTOR pathway. The results elucidate a potential mechanism underlying the tumor‐suppressor role of CISD2 and it is expected that screening CISD2 expression combined chemotherapy drugs will become the new therapy strategy for gastric cancer.