Abstract
The mechanisms by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in colorectal cancer cells are undergoing intensive investigation. We found previously that NSAIDs induce apoptosis in these cells by restoring 15-lipoxygenase-1 (15-LOX-1) expression. The present study examined the NSAID mechanism for up-regulating 15-LOX-1 in two colorectal cancer cell lines (RKO and DLD-1). We found that NSAID effects on 15-LOX-1 occurred at the level of transcriptional regulation. We then studied NSAID effects on GATA-6, a transcription factor that suppresses 15-LOX-1 expression. Beginning within 4 h, NSAIDs progressively down-regulated GATA-6 expression. Ectopic GATA-6 expression blocked NSAID induction of 15-LOX-1 and apoptosis. NSAIDs down-regulate GATA-6 to transcriptionally up-regulate 15-LOX-1 and induce apoptosis in colorectal cancer cells.
Publication types
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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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Apoptosis / drug effects*
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Apoptosis / genetics
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Arachidonate 15-Lipoxygenase / biosynthesis*
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Arachidonate 15-Lipoxygenase / genetics
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Cell Division / drug effects
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Colorectal Neoplasms / enzymology*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / pathology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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GATA6 Transcription Factor
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Sulindac / pharmacology
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic
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Transfection
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Tumor Cells, Cultured
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Up-Regulation / drug effects
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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DNA-Binding Proteins
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GATA6 Transcription Factor
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GATA6 protein, human
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Transcription Factors
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Sulindac
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Arachidonate 15-Lipoxygenase