Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which has long been believed to be highly selective in inducing apoptosis in cancer cells, has turned out to be a molecule that induces a far more diverse range of effects. The aim of this study was to investigate whether or not ERK1/2 pathway is involved in antitumor effects of TRAIL on gastric cancer cells. In addition to activate the extrinsic and intrinsic apoptotic pathway, TRAIL also triggered the activation of ERK1/2. Inhibition of ERK1/2 signaling by MEK inhibitor U0126 promoted cell death via increased activation of caspases, drop in mitochondrial membrane potential and downregulation of XIAP, cIAP2 and Mcl-1. These results indicate that TRAIL-induced rapid activation of ERK1/2 may be a survival mechanism to struggle against TRAIL assault at the early stage, and inhibition of ERK1/2 signaling can sensitize gastric cancer cells to TRAIL-induced apoptosis.
Keywords:
gastric cancer, TRAIL, ERK1/2, apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / genetics*
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Apoptosis Regulatory Proteins / genetics
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Baculoviral IAP Repeat-Containing 3 Protein
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Butadienes / pharmacology
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Cell Line, Tumor
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Down-Regulation
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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MAP Kinase Kinase Kinases / metabolism*
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MAP Kinase Signaling System / drug effects
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Nitriles / pharmacology
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Stomach Neoplasms / pathology
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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Ubiquitin-Protein Ligases
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Butadienes
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Inhibitor of Apoptosis Proteins
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitriles
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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U 0126
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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MAP Kinase Kinase Kinases