Abstract
We studied potential interactions between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway. Induction of ER stress did not trigger significant apoptosis, but caused rapid activation of ERK1/2 in gastric cancer cells. Inhibition of MEK enhanced ER stress-induced apoptosis via a caspase-dependent, mitochondria-mediated mechanism. This was associated with blockage of ER stress-mediated up-regulation of GRP78. The latter appeared to be critical in antagonizing the apoptosis-inducing potential of ER stress. Thus, activation of MEK/ERK by ER stress is necessary for induction of GRP78 that protects against apoptosis in gastric cancer cells submitted to ER stress.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 6 / antagonists & inhibitors
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Activating Transcription Factor 6 / genetics
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Activating Transcription Factor 6 / metabolism
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Antiviral Agents / pharmacology
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Apoptosis*
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Blotting, Western
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Caspases / metabolism
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Endoplasmic Reticulum / drug effects*
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Endoplasmic Reticulum Chaperone BiP
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Endoribonucleases / antagonists & inhibitors
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Endoribonucleases / genetics
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Endoribonucleases / metabolism
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Enzyme Inhibitors / pharmacology
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Heat-Shock Proteins / metabolism*
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Humans
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MAP Kinase Kinase 1 / antagonists & inhibitors*
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 1 / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Molecular Chaperones / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / 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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Thapsigargin / pharmacology
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Tumor Cells, Cultured
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Tunicamycin / pharmacology
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Up-Regulation
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eIF-2 Kinase / antagonists & inhibitors
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism
Substances
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Activating Transcription Factor 6
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Antiviral Agents
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Endoplasmic Reticulum Chaperone BiP
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Enzyme Inhibitors
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HSPA5 protein, human
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Heat-Shock Proteins
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Molecular Chaperones
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RNA, Small Interfering
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Tunicamycin
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Thapsigargin
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ERN1 protein, human
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Endoribonucleases
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Caspases