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

Brian Leibowitz, Wei Qiu, Monica E. Buchanan, Fangdong Zou, Philip Vernon, Mary P. Moyer, Xiao Ming Yin, Robert E. Schoen, Jian Yu, Lin Zhang

Research output: Contribution to journalArticle

16 Scopus citations

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 APCMin/+ 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.

Original languageEnglish (US)
Pages (from-to)16520-16525
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number46
DOIs
StatePublished - Nov 18 2014

ASJC Scopus subject areas

  • General

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