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Non-steroidal anti-inflammatory drugs induce immunogenic cell death in suppressing colorectal tumorigenesis

Oncogene volume 40, pages 2035–2050 (2021)Cite this article

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Abstract

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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Fig. 1: ER stress mediates the killing effect of sulindac sulfide in HCT116 cells.
Fig. 2: ER stress mediates the killing effect of indomethacin and other NSAIDs in HCT116 cells.
Fig. 3: ER stress mediates the killing effect of sulindac sulfide on non-transformed colonic epithelial cells with APC loss.
Fig. 4: NSAID-induced apoptosis is immunogenic cell death.
Fig. 5: Inhibition of ER stress suppresses the chemopreventive and apoptotic effects of sulindac in APCMin/+ mice.
Fig. 6: ER stress inhibition and BID KO suppresses NSAID-mediated immune cell infiltration.
Fig. 7: Induction of apoptosis, ER stress, and lymphocyte infiltration in advanced adenomas from NSAID-treated patients.

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Acknowledgements

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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Authors and Affiliations

  1. UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Rochelle Fletcher, Jingshan Tong, Denise Risnik, Brian J. Leibowitz, Yi-Jun Wang, Fernando Concha-Benavente, Donna B. Stolz, Reet K. Pai, Robert L. Ferris, Robert E. Schoen, Jian Yu & Lin Zhang

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Rochelle Fletcher, Jingshan Tong, Denise Risnik, Yi-Jun Wang, Jonathan M. DeLiberty & Lin Zhang

  3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Brian J. Leibowitz, Reet K. Pai & Jian Yu

  4. Departments of Otolaryngology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Fernando Concha-Benavente & Robert L. Ferris

  5. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Donna B. Stolz

  6. Departments of Medicine and Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Robert E. Schoen

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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

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