Chemotherapeutic drugs-induced pyroptosis mediated by gasdermin E promotes the progression and chemoresistance of pancreatic cancer
Chemotherapeutic drugs-induced pyroptosis mediated by gasdermin E promotes the progression and chemoresistance of pancreatic cancer
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DOI：
10.1016/j.canlet.2023.216206
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发表时间：
2023-05-03
期刊：
影响因子：
9.7
通讯作者：
Wang, Liwei
中科院分区：
文献类型：
--
作者：
Li, Shumin;Yue, Ming;Wang, Liwei
焦亡与癌症发展密切相关;然而，焦亡在胰腺导管腺癌（PDAC）中的作用仍然难以捉摸，PDAC是一种致命的恶性肿瘤，总生存率很低。在这里，我们探讨了化疗诱导的细胞凋亡的机制，并阐明了细胞凋亡在介导PDAC进展和化疗耐药性中的作用。结果表明，针对PDAC的一线和二线化疗药物，包括吉西他滨、伊立替康、5-氟尿嘧啶、紫杉醇和顺铂，诱导了并发的焦亡和细胞凋亡。在此过程中，gasdermin E（GSDME）被激活的caspase-3裂解，这伴随着促凋亡caspase-7/8激活。GSDME基因敲低可使PDAC细胞由凋亡转为焦亡，降低其侵袭和迁移能力，增强其对化疗药物的敏感性。GSDME在PDAC组织中高表达，并与组织分化程度、血管浸润程度呈正相关。此外，细胞存活pyroptosis促进增殖和侵袭，并损害PDAC细胞的化疗敏感性，这是减弱的GSDME敲低。我们的研究结果表明，针对PDAC的化疗药物诱导GSDME依赖性焦亡，并且GSDME表达与PDAC进展和化疗耐药性正相关。靶向GSDME可能是克服PDAC化疗耐药性的一种新方法。
Pyroptosis is closely associated with cancer development; however, the role of pyroptosis in pancreatic ductal adenocarcinoma (PDAC), a fatal malignant tumour with a poor overall survival rate, remains elusive. Here, we explored the mechanism of chemotherapy-induced pyroptosis and elucidated the role of pyroptosis in mediating PDAC progression and chemoresistance. The results demonstrated first- and second-line chemotherapeutic drugs against PDAC, including gemcitabine, irinotecan, 5-fluorouracil, paclitaxel, and cisplatin, induced concurrent pyroptosis and apoptosis. During this process, gasdermin E (GSDME) was cleaved by activated caspase-3, which was accompanied by pro-apoptotic caspase-7/8 activation. GSDME knockdown switched pyroptosis to apoptosis, decreased invasion and migration, and enhanced the sensitivity of PDAC cells to chemotherapy in vitro and in vivo. GSDME was highly expressed in PDAC tissues and positively correlated with histological differentiation and vascular invasion. Furthermore, cells that survived pyroptosis promoted proliferation and invasion and impaired the chemosensitivity of PDAC cells, which was attenuated by the GSDME knockdown. Our findings demonstrated that chemotherapeutics against PDAC induce GSDME-dependent pyroptosis, and GSDME expression positively correlated with PDAC progression and chemoresistance. Targeting GSDME may be a novel approach to overcoming chemoresistance in PDAC.