Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

上睑下垂 癌症研究 胰腺癌 癌症 生物 肺癌 癌细胞 程序性细胞死亡 医学 免疫学 细胞凋亡 肿瘤科 遗传学 生物化学
作者
Liangping Su,Yitian Chen,Cheng Huang,Sangqing Wu,Xiaojuan Wang,Xinbao Zhao,Qiuping Xu,Ruipu Sun,Xiangzhan Kong,Xue Jiang,Xiaoyi Qiu,Xiaoming Huang,Minghui Wang,Ping‐Pui Wong
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:15 (678) 被引量:46
标识
DOI:10.1126/scitranslmed.abl7895
摘要

Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src-signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.
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