未折叠蛋白反应
免疫监视
结直肠癌
癌症研究
生物
内质网
细胞凋亡
免疫原性细胞死亡
癌症
程序性细胞死亡
癌变
免疫学
炎症
内科学
医学
细胞生物学
肿瘤细胞
生物化学
作者
Rochelle Fletcher,Jingshan Tong,Denise Risnik,Brian J. Leibowitz,Yijun Wang,Fernando Concha-Benavente,Jonathan M. DeLiberty,Donna B. Stolz,Reet Pai,Robert L. Ferris,Robert E. Schoen,Jian Yu,Lin Zhang
出处
期刊:Oncogene
[Springer Nature]
日期:2021-02-18
卷期号:40 (11): 2035-2050
被引量:21
标识
DOI:10.1038/s41388-021-01687-8
摘要
Use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal cancer (CRC). However, the mechanism by which NSAIDs suppress colorectal tumorigenesis remains unclear. We previously showed that NSAIDs selectively kill emerging tumor cells via death receptor (DR) signaling and a synthetic lethal interaction mediated by the proapoptotic Bcl-2 family protein BID. In this study, we found NSAIDs induce endoplasmic reticulum (ER) stress to activate DR signaling and BID in tumor suppression. Importantly, our results unveiled an ER stress- and BID-dependent immunogenic effect of NSAIDs, which may be critical for tumor suppression. NSAID treatment induced hallmarks of immunogenic cell death (ICD) in CRC cells and colonic epithelial cells upon loss of APC tumor suppressor, and elevated tumor-infiltrating lymphocytes (TILs) in the polyps of APCMin/+ mice. ER stress inhibition or BID deletion abrogated the antitumor and immunogenic effects of NSAIDs. Furthermore, increased ER stress and TILs were detected in human advanced adenomas from NSAID-treated patients. Together, our results suggest that NSAIDs induce ER stress- and BID-mediated ICD to restore immunosurveillance and suppress colorectal tumor formation.
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