Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
Cell Biol Int. 2020 Sep;44(9):1890-1899. doi: 10.1002/cbin.11395. Epub 2020 Jun 8.
Adjuvant chemotherapy in combination with surgery is expected to be a curative strategy for gastric cancer. However, drug resistance remains an obstacle in effective chemotherapy. Therefore, understanding the potential mechanisms of chemotherapy induced gastric cancer cell death is of great importance. We demonstrated that BIX-01294 (BIX) at low concentration could induce autophagic flux by converting LC3B-I to LC3B-II and directly activate autophagy associated cell death in gastric cancer cell lines at high concentration. BIX at low concentration could help obtain sensitivity of gastric cancer cells to chemotherapy with significantly reduced cell viability. Interestingly, BIX combined Cis (BIX + Cis) treated SGC-7901 cells display pyroptosis related cell death with large bubbles blown around the membrane, significantly decreased cell viability, elevated lactate dehydrogenase release and increased percentage of propidium iodide and Annexin-V double positive cells. Furthermore, the cleavage of gasdermin E (GSDME) and caspase-3 but not GSDMD was detected by immunoblotting and the knockout of GSDME switched pyroptosis into apoptosis in the BIX + Cis combined treated group. Furthermore, the deficiency of Beclin-1 to inhibit BIX induced autophagic flux completely blocked BIX + Cis combined treated induced cell pyroptosis related cell death. Additionally, BIX + Cis in vivo treatment could inhibit tumor growth, which could be reversed by the deficiency of Beclin-1 and be delayed by the deficiency of GSDME. In conclusion, our data was the first to reveal that BIX enhanced the anticancer chemotherapy effect by induced GSDME-mediated pyroptosis through the activation of autophagic flux in gastric cancer cells.
辅助化疗联合手术有望成为治疗胃癌的一种有治愈前景的策略。然而，耐药性仍然是有效化疗的一个障碍。因此，了解化疗诱导胃癌细胞死亡的潜在机制非常重要。我们证明，低浓度的 BIX-01294（BIX）可以通过将 LC3B-I 转化为 LC3B-II 来诱导自噬流，并在高浓度下直接激活与自噬相关的胃癌细胞死亡。低浓度的 BIX 可以帮助获得胃癌细胞对化疗的敏感性，同时显著降低细胞活力。有趣的是，BIX 联合顺铂（BIX+Cis）处理的 SGC-7901 细胞表现出与细胞焦亡相关的死亡，细胞膜周围有大泡鼓起，细胞活力显著下降，乳酸脱氢酶释放增加，碘化丙啶和 Annexin-V 双阳性细胞的比例增加。此外，免疫印迹检测到天冬氨酸特异性半胱氨酸蛋白酶-3（caspase-3）和 Gasdermin E（GSDME）的裂解，但未检测到 GSDMD 的裂解。BIX+Cis 联合处理组中 GSDME 的敲除将细胞焦亡转化为细胞凋亡。此外，Beclin-1 的缺失抑制 BIX 诱导的自噬流完全阻断了 BIX+Cis 联合处理诱导的细胞焦亡相关细胞死亡。此外，BIX+Cis 体内治疗可以抑制肿瘤生长，这种作用可以被 Beclin-1 的缺失逆转，也可以被 GSDME 的缺失延迟。总之，我们的数据首次揭示，BIX 通过激活自噬流增强了胃癌细胞中 GSDME 介导的细胞焦亡，从而增强了抗癌化疗的效果。
