Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells.
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.
Zhang
Lin Jie
LJ
Department Immunology, Anhui Medical University, PR China.
Chen
Si
S
Wu
Pin
P
Hu
Chun Song
CS
Thorne
Rick F
RF
Luo
Chang Ming
CM
Hersey
Peter
P
Zhang
Xu Dong
XD
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
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