期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：16520-16525
DOI：10.1073/pnas.1415178111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceColorectal cancer is the third leading cause of cancer-related death in the United States, but treatment options for this disease are of limited effectiveness. Most human colorectal tumors begin with an inactivating mutation in the adenomatous polyposis coli (APC) gene. We demonstrate a mechanism by which nonsteroidal antiinflammatory drugs (NSAIDs) protect against colon cancer development by killing intestinal stem cells that have lost functional APC. NSAID treatment combines with APC loss-induced gene expression changes to selectively activate BID and induce apoptosis in these cells, while leaving normal cells unharmed. These results provide a rationale for developing more effective cancer prevention strategies and agents. 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.
关键词：colorectal cancer ; APC ; chemoprevention ; BID ; apoptosis
