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.
authors.affiliation: University of Pittsburgh Cancer Institute, Departments of Pathology.
authors.forename: Brian
authors.initials: B
authors.lastname: Leibowitz
authors.affiliation: University of Pittsburgh Cancer Institute, Departments of Pathology.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.affiliation: University of Pittsburgh Cancer Institute, Pharmacology & Chemical Biology, and.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Buchanan
authors.affiliation: University of Pittsburgh Cancer Institute, Pharmacology & Chemical Biology, and College of Life Sciences, Sichuan University, Chengdu, Sichuan, 610064, P.R. China;
authors.forename: Fangdong
authors.initials: F
authors.lastname: Zou
authors.affiliation: University of Pittsburgh Cancer Institute.
authors.forename: Philip
authors.initials: P
authors.lastname: Vernon
authors.affiliation: INCELL Corporation, San Antonio, TX 78249; and.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Departments of Pathology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
authors.affiliation: University of Pittsburgh Cancer Institute, Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schoen
authors.affiliation: University of Pittsburgh Cancer Institute, Departments of Pathology, zhanglx@upmc.edu yuj2@upmc.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: University of Pittsburgh Cancer Institute, Pharmacology & Chemical Biology, and zhanglx@upmc.edu yuj2@upmc.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D003106:Colon / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D016259:Genes, myc; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009928:Organ Specificity; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D053218:Receptors, Death Domain / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D020169:Caspases; D007213:Indomethacin; D011720:Pyrazoles; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D013449:Sulfonamides; D013467:Sulindac; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C494814:BID protein, human; C494815:Bid protein, mouse
keywords: APC; BID; apoptosis; chemoprevention; colorectal cancer