BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs Journal Article

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Authors: Leibowitz, B.; Qiu, W; Buchanan, M. E.; Zou, F.; Vernon, P.; Moyer, M. P.; Yin, X. M.; Schoen, R. E.; Yu, J; Zhang, L
Article Title: BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs
Abstract: Colorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 111
Issue: 46
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: 16520
End Page: 16525
Language: eng
DOI/URL:

10.1073/pnas.1415178111
Notes: LR: 20141203; GR: CA106348/CA/NCI NIH HHS/United States; GR: CA121105/CA/NCI NIH HHS/United States; GR: CA129829/CA/NCI NIH HHS/United States; GR: CA172136/CA/NCI NIH HHS/United States; GR: P30CA047904/CA/NCI NIH HHS/United States; GR: U01DK085570/DK/NIDDK NIH HHS/United States; JID: 7505876; OID: NLM: PMC4246283 [Available on 05/18/15]; OTO: NOTNLM; PMCR: 2015/05/18 00:00; 2014/11/03 [aheadofprint]; ppublish