title: Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells.
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.
authors.affiliation: Department Immunology, Anhui Medical University, PR China.
authors.forename: Lin Jie
authors.initials: LJ
authors.lastname: Zhang
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.forename: Pin
authors.initials: P
authors.lastname: Wu
authors.forename: Chun Song
authors.initials: CS
authors.lastname: Hu
authors.forename: Rick F
authors.initials: RF
authors.lastname: Thorne
authors.forename: Chang Ming
authors.initials: CM
authors.lastname: Luo
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D000998:Antiviral Agents; D020169:Caspases; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D019284:Thapsigargin; D014415:Tunicamycin; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C528229:ERN1 protein, human; C482125:MAP2K1 protein, human