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.
Keywords:
APC; BID; apoptosis; chemoprevention; colorectal cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli / pathology
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Adenomatous Polyposis Coli / prevention & control*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Apoptosis Regulatory Proteins / physiology
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Apoptosis*
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BH3 Interacting Domain Death Agonist Protein / antagonists & inhibitors
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BH3 Interacting Domain Death Agonist Protein / deficiency
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BH3 Interacting Domain Death Agonist Protein / genetics
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BH3 Interacting Domain Death Agonist Protein / physiology*
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Caspases / physiology
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Cell Line, Tumor
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Colon / pathology
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Gene Expression Regulation, Neoplastic
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Genes, APC*
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Genes, myc
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Humans
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Indomethacin / pharmacology
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Intestine, Small / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mitochondria / metabolism
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Organ Specificity
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Pyrazoles / pharmacology
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RNA, Small Interfering / pharmacology
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Receptors, Death Domain / physiology
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Stem Cells / metabolism
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Stem Cells / pathology
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Sulfonamides / pharmacology
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Sulindac / pharmacology
Substances
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4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
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Anti-Inflammatory Agents, Non-Steroidal
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Bid protein, mouse
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Pyrazoles
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RNA, Small Interfering
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Receptors, Death Domain
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Sulfonamides
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Sulindac
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Caspases
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Indomethacin