Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis / physiology
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CASP8 and FADD-Like Apoptosis Regulating Protein / biosynthesis
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Drug Resistance, Neoplasm
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Humans
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Male
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Mice
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Mice, Nude
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins c-fos / metabolism*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Recombinant Proteins / pharmacology
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Transcription Factor AP-1 / metabolism
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Xenograft Model Antitumor Assays
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Transcription Factor AP-1