BIX-01294 enhanced chemotherapy effect in gastric cancer by inducing GSDME-mediated pyroptosis
BIX-01294 enhanced chemotherapy effect in gastric cancer by inducing GSDME-mediated pyroptosis
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DOI：
10.1002/cbin.11395
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发表时间：
2020-06-08
影响因子：
3.9
通讯作者：
Wang, Gui-Jun
中科院分区：
文献类型：
--
作者：
Deng, Bei-Bei;Jiao, Bao-Ping;Wang, Gui-Jun
辅助化疗联合手术有望成为胃癌的一种治疗策略。然而，耐药性仍然是有效化疗的障碍。因此，了解化疗诱导胃癌细胞死亡的潜在机制具有重要意义。我们证明BIX-01294 （BIX）在低浓度时可以通过将LC3B-I转化为LC3B-II诱导自噬通量，并在高浓度时直接激活自噬相关的胃癌细胞系细胞死亡。低浓度BIX可以帮助获得胃癌细胞对化疗的敏感性，但显著降低细胞活力。有趣的是，BIX联合Cis （BIX + Cis）处理的SGC-7901细胞表现出焦亡相关的细胞死亡，膜周围吹出大气泡，细胞活力显著降低，乳酸脱氢酶释放升高，碘化丙啶和膜联蛋白v双阳性细胞百分比增加。此外，免疫印迹法检测到GSDME和caspase-3的裂解，而非GSDMD的裂解，并且在BIX + Cis联合处理组中，GSDME的敲除将焦亡转变为凋亡。此外，缺乏抑制BIX诱导的自噬通量的Beclin-1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在体内治疗可抑制肿瘤生长，这种抑制可因Beclin-1缺乏而逆转，并因GSDME缺乏而延迟。综上所述，我们的数据首次揭示了BIX通过激活胃癌细胞的自噬通量，诱导gsdme介导的焦亡，从而增强了抗癌化疗的效果。
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.