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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The authors thank Dr. Michael T. Lotze and our lab members for discussion and critical reading and Ms. Dorothy Coe for technical assistance. This work is supported by U.S. National Institute of Health grants (R01CA172136, R01CA203028, R01CA217141, R01CA236271, and R01CA247231 to LZ; U19AI068021 and R01CA215481 to JY; U01CA152753 to RES). This project used the UPMC Hillman Cancer Center shared facilities that were supported in part by award P30CA047904.
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Fletcher, R., Tong, J., Risnik, D. et al. Non-steroidal anti-inflammatory drugs induce immunogenic cell death in suppressing colorectal tumorigenesis. Oncogene 40, 2035–2050 (2021). https://doi.org/10.1038/s41388-021-01687-8