Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
Biomed Pharmacother. 2020 May;125:109896. doi: 10.1016/j.biopha.2020.109896. Epub 2020 Jan 30.
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.
顺铂（DDP）是治疗胃癌（GC）的一线药物。然而，DDP 耐药很常见。自噬与化疗耐药密切相关，是一种解决和回收蛋白质和受损细胞器官的过程。此外，O-6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）负责烷基化耐药。然而，GC 中自噬和 MGMT 对 DDP 反应的关系尚不清楚。在本研究中，我们确定 DDP 诱导的自噬降低了 GC 细胞系的化疗敏感性。DDP 可能通过抑制 MGMT 增加自噬相关基因（ATG）4B 来诱导 GC 中的自噬。抑制 MGMT 介导的 ATG4B 抑制导致自噬诱导和 DDP 耐药。在体内，DDP 与自噬抑制剂氯喹（CQ）联合使用增强了 DDP 的抗肿瘤作用；此外，还证实了 MGMT 和 ATG4B 的负相关。在 66 例临床病理特征明确的 GC 病例中，高表达 MGMT 和低表达 ATG4B 与良好的五年生存率显著相关（P<0.05）。我们的研究表明，DDP 通过抑制 MGMT 介导的自噬抑制来降低 GC 的化疗敏感性，为提高 GC 中 DDP 的化疗敏感性提供了一种新的治疗策略。
