1. Inhibition of MGMT-mediated autophagy suppression decreases cisplatin chemosensitivity in gastric cancer.
- Author
-
Lei Y, Tang L, Hu J, Wang S, Liu Y, Yang M, Zhang J, and Tang B
- Subjects
- Animals, Antineoplastic Agents pharmacology, Autophagy physiology, Biomarkers, Tumor antagonists & inhibitors, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cisplatin pharmacology, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm physiology, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Random Allocation, Stomach Neoplasms drug therapy, Xenograft Model Antitumor Assays methods, Antineoplastic Agents therapeutic use, Autophagy drug effects, Cisplatin therapeutic use, DNA Modification Methylases antagonists & inhibitors, DNA Modification Methylases metabolism, DNA Repair Enzymes antagonists & inhibitors, DNA Repair Enzymes metabolism, Stomach Neoplasms metabolism, Tumor Suppressor Proteins antagonists & inhibitors, Tumor Suppressor Proteins metabolism
- Abstract
Cisplatin (DDP) is the first-line drug for the treatment of gastric cancer (GC). However, DDP resistance is common. Autophagy, which is closely related to chemoresistance, is a process of resolving and recycling proteins and damaged cellular organs. Additionally, O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for alkylating drug resistance. However, the relationship between autophagy and MGMT in response to DDP in GC is still unknown. In the present study, we determined that autophagy induced by DDP decreases chemosensitivity in GC cell lines. DDP may have induced autophagy in GC by inhibiting MGMT to increase autophagy-related gene (ATG) 4B. Inhibition of MGMT-mediated ATG4B suppression resulted in autophagy induction and DDP resistance. In vivo, combined DDP and autophagy inhibitor chloroquine (CQ) enhanced the anti-tumor effect of DDP; additionally, the negative correlation of MGMT and ATG4B was confirmed. High expression of MGMT and low expression of ATG4B were significantly correlated with favorable five-year survival rate (P < 0.05) in 66 clinicopathologically characterized GC cases. Our study demonstrate that DDP inhibits MGMT-mediated autophagy suppression to decrease chemosensitivity in GC, which provides a novel therapeutic strategy to promote DDP chemosensitivity in GC., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF