title: Inhibition of MEK sensitizes paclitaxel-induced apoptosis of human colorectal cancer cells by downregulation of GRP78.
abstract: Here we report that paclitaxel induces variable degrees of apoptosis in human colorectal cancer cells. Paclitaxel induces multiple arms of the endoplasmic reticulum stress response, including upregulation of the 78-kDa glucose-regulatory protein (GRP78) and eukaryotic initiation factor alpha phosphorylation. Inhibition of the MEK/ERK pathway sensitized colorectal cancer cells to paclitaxel-induced apoptosis. A similar result was obtained by the inhibition of GRP78 using small interfering RNA molecules. Knockdown of MEK resulted in a significant downregulation of paclitaxel-induced upregulation of GRP78 indicating that activation of GRP78 is a downstream event of MEK/ERK pathway activation. These results indicate that GRP78 might be a novel mechanism underlying the resistance of colorectal cancer cells to microtubule-targeting drugs. A combination of compounds capable of suppressing GRP78 might be a golden approach for improving the effectiveness of taxanes.
authors.affiliation: Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan. nizarm@just.edu.jo
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Mhaidat
authors.forename: Feras Q
authors.initials: FQ
authors.lastname: Alali
authors.forename: Sina M
authors.initials: SM
authors.lastname: Matalqah
authors.forename: Ismail I
authors.initials: II
authors.lastname: Matalka
authors.forename: Saied A
authors.initials: SA
authors.lastname: Jaradat
authors.forename: Nour A
authors.initials: NA
authors.lastname: Al-Sawalha
authors.forename: Rick F
authors.initials: RF
authors.lastname: Thorne
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel