title: Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis.
abstract: Accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces ER stress which is observed in many human diseases, including breast cancer. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. Higher levels of GRP78 expression indicates constitutive activation of the UPR in breast cancer leading to breast cancer cells that are relatively resistant to ER stress-induced apoptosis. Tunicamycin (TM), an ER stress inducer, constitutively activates the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK), and (MEK)/ERK pathway which plays a role in upregulation of GRP78 by ER stress in that inhibition of MEK by U0126 reduces the levels of GRP78 and blocks its upregulation by TM. Inhibition of the MEK/ERK pathway by U0126 sensitizes breast cancer cells to TM-induced apoptosis. Inhibition of GRP78 by siRNA knockdown enhances TM- and U0126-induced apoptosis in breast cancer cells. This sensitization of breast cancer cells to TM-induced apoptosis by inhibition of MEK/ERK and GRP78 is caspase-dependent, at least in part, by activation of caspase-4. These results seem to indicate that GRP78 has potential as a chemotherapeutical target and have important implications for new treatment strategies in breast cancer by combination with agents that induce ER stress with inhibitors of the MEK/ERK pathway.
authors.affiliation: Department of Tumor Radiotherapy, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, P.R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, Nanjing Chest Hospital, Nanjing, Jiangsu, P.R. China.
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Tang
authors.affiliation: Department of Pharmacy, Bengbu Medical College, Bengbu, Anhui, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Bengbu Medical College, Bengbu, Anhui, P.R. China.
authors.forename: Zhi Wen
authors.initials: ZW
authors.lastname: Jiang
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D009570:Nitriles / Q000494:pharmacology*; D014415:Tunicamycin / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D002070:Butadienes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009570:Nitriles; C113580:U 0126; D014415:Tunicamycin; D020169:Caspases