School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China.
First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471000, People's Republic of China.
Can J Physiol Pharmacol. 2020 Jul;98(7):449-458. doi: 10.1139/cjpp-2019-0477. Epub 2020 Feb 14.
Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the sensitivity and resistance of gastric cancer cells to cisplatin (DDP). We firstly demonstrated that there was stronger autophagy activity in gastric cancer SGC-7901 cells than that in DDP-resisting SGC-7901/DDP cells. Then, we discovered that inhibiting autophagy by chloroquine (CQ) significantly enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP to SGC-7901 and SGC-7901/DDP cells. Moreover, CQ could partially reverse the resistance of SGC-7901/DDP cells to DDP in a concentration-dependent manner. However, the autophagy inducer everolimus (RAD001) had no obvious effects on the sensitivity of gastric cells to DDP. Mechanistically, we demonstrated that CQ might enhance the sensitivity of SGC-7901cells and improve the resistance of SGC-7901/DDP cells to DDP through inhibiting the mTORC1 pathway, especially to SGC-7901/DDP cells. Additionally, we found interfering Beclin-1 using Beclin-1 shRNA also enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP on gastric cancer cells by inhibiting phosphorylation of Akt. Our study shows that inhibiting autophagy could improve the chemoresistance and enhanced sensitivity of gastric cancer cells to DDP and provide a rationale for the administration of cisplatin combined with CQ for treating patients with gastric cancer.
自噬在肿瘤发生中发挥着关键作用，而自噬对癌细胞化疗耐药性的影响存在很大差异。本研究旨在探讨自噬对胃癌细胞对顺铂（DDP）敏感性和耐药性的影响。我们首先证明胃癌 SGC-7901 细胞中的自噬活性强于耐药性 SGC-7901/DDP 细胞。然后，我们发现通过氯喹（CQ）抑制自噬显著增强了 DDP 对 SGC-7901 和 SGC-7901/DDP 细胞的增殖抑制和凋亡诱导作用。此外，CQ 可以部分地以浓度依赖性方式逆转 SGC-7901/DDP 细胞对 DDP 的耐药性。然而，自噬诱导剂依维莫司（RAD001）对胃癌细胞对 DDP 的敏感性没有明显影响。在机制上，我们证明 CQ 可能通过抑制 mTORC1 通路，特别是对 SGC-7901/DDP 细胞，增强 SGC-7901 细胞的敏感性并提高 SGC-7901/DDP 细胞对 DDP 的耐药性。此外，我们发现使用 Beclin-1 shRNA 干扰 Beclin-1 也通过抑制 Akt 的磷酸化增强了 DDP 对胃癌细胞的增殖抑制和凋亡诱导作用。我们的研究表明，抑制自噬可以提高胃癌细胞对 DDP 的化疗耐药性和敏感性，并为联合顺铂和 CQ 治疗胃癌患者提供了理论依据。
