Abstract
To assess the role of BAX in drug-induced apoptosis in human colorectal cancer cells, we generated cells that lack functional BAX genes. Such cells were partially resistant to the apoptotic effects of the chemotherapeutic agent 5-fluorouracil, but apoptosis was not abolished. In contrast, the absence of BAX completely abolished the apoptotic response to the chemopreventive agent sulindac and other nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibited the expression of the antiapoptotic protein Bcl-XL, resulting in an altered ratio of BAX to Bcl-XL and subsequent mitochondria-mediated cell death. These results establish an unambiguous role for BAX in apoptotic processes in human epithelial cancers and may have implications for cancer chemoprevention strategies.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Anticarcinogenic Agents / pharmacology
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Antimetabolites, Antineoplastic / pharmacology*
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Apoptosis*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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Fluorouracil / pharmacology*
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Genes, p53
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Humans
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Indomethacin / pharmacology
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Intracellular Membranes / drug effects
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Intracellular Membranes / physiology
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Membrane Potentials / drug effects
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Mitochondria / drug effects
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Mitochondria / physiology
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Mutation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogenes
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Sulindac / pharmacology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Anticarcinogenic Agents
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Antimetabolites, Antineoplastic
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BAX protein, human
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BCL2L1 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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bcl-X Protein
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Sulindac
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Fluorouracil
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Indomethacin