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The Role of NSAID-Induced ER Stress and Immunomodulation in the Suppression of Colorectal Tumorigenesis

Fletcher, Rochelle (2018) The Role of NSAID-Induced ER Stress and Immunomodulation in the Suppression of Colorectal Tumorigenesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Prevention or early detection represents a key approach for reducing the mortality and morbidity of colorectal cancer (CRC). Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of CRC in numerous epidemiological studies, clinical trials, and animal model studies. However, the mechanism by which NSAIDs suppress colorectal tumorigenesis has remained unclear. We previously demonstrated that the chemopreventive effect of NSAIDs is mediated by a synthetic lethal interaction between death receptor signaling and loss of the gatekeeper APC tumor suppressor, which is dependent on the BH3-only Bcl-2 family member BID. In this study, we found a critical role of endoplasmic reticulum (ER) stress upstream of death receptor signaling and BID activation. Elevated levels of ER stress and cell death markers were detected in advanced adenomas from patients taking NSAIDs including aspirin. Inhibiting ER stress using a pharmacological approach abolished the apoptotic effect of NSAIDs in CRC cells and normal colonic epithelial cells with APC loss and also suppressed the chemopreventive activity of the NSAID sulindac in APCMin/+ mice. Importantly, our results unveiled a critical role of ER stress and BID-dependent cell death in triggering immune-mediated elimination of nascent cells that lose APC. Markers of immunogenic cell death (ICD), including plasma membrane translocation of calreticulin and phagocytosis by dendritic cells, were suppressed in cells with BID knockout or ER stress inhibition. BID knockout or ER stress inhibition also reduced tumor-infiltrating lymphocytes (TILs) in sulindac-treated APCMin/+ mice. Collectively, our results suggest that NSAIDs suppress colorectal tumorigenesis by enhancing immunosurveillance through ER stress and BID-dependent ICD. These results provide novel insight into the chemopreventive mechanism of NSAIDs, which may help to design more effective chemopreventive strategies and agents.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fletcher, Rochelleref48@pitt.eduref48
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKensler, Thomastkensler@pitt.edutkensler
Thesis AdvisorZhang, Linzhanglx@upmc.edu
Committee MemberStolz, Donnadonna.stolz@pitt.edudonna.stolz
Committee MemberWang, Janeqjw1@pitt.eduqjw1
Committee MemberO'Sullivan, Roddyosullivanr@upmc.edu
Date: 2 May 2018
Date Type: Publication
Defense Date: 9 April 2018
Approval Date: 2 May 2018
Submission Date: 1 May 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 128
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: NSAIDs, CRC, ER stress, Prevention, Immunomodulation
Date Deposited: 02 May 2018 14:33
Last Modified: 04 Jun 2018 15:39
URI: http://d-scholarship.pitt.edu/id/eprint/34470

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