title: CHM-1 Suppresses Formation of Cell Surface-associated GRP78-p85α Complexes, Inhibiting PI3K-AKT Signaling and Inducing Apoptosis of Human Nasopharyngeal Carcinoma Cells.
abstract: The endoplasmic reticulum chaperone glucose-regulated protein 78 (GRP78) is selectively expressed on the surface of cancer cells, and contributes to the survival of cancer cells by forming complexes with p85α and promoting phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling. Hereιin we report that 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) induces apoptosis of human nasopharyngeal carcinoma (NPC) cells, as characterized by morphological changes, DNA fragmentation, caspase-3 activation, and cleavage of poly (ADP-ribose) polymerase. Using cell surface biotinylation, flow cytometric analysis, co-immunoprecipitation, and ectopic expression of GRP78, we demonstrated that the attenuation of the cell surface localization and complex formation with p85α of GRP78 by CHM-1 was involved in the inhibition of PI3K-AKT signaling and the induction of apoptosis. CHM-1 treatment induced phosphorylation on Thr 69 of B cell lymphoma 2 and inhibited phosphorylation of Ser 136 on Bcl-2-associated death promoter, that were reversed by overexpression of GRP78. We further observed that loss of mitochondrial membrane potential and increase in reactive oxygen species content, release of mitochondrial cytochrome c, caspase-9 activation, and apoptotic cell death induced by CHM-1, were suppressed by treatment with cyclosporine A, and by the overexpression of constitutively active AKT1 or GRP78. These results indicate that CHM-1 induces NPC cell apoptosis by suppressing the formation of the cell surface-associated GRP78-PI3K-AKT signaling complex, likely through inhibition of the formation of cell surface-associated GRP78-p85α complexes.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, R.O.C. mllinsally@yahoo.com.tw.
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Lin
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C.
authors.forename: Shih-Shun
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C.
authors.forename: Sue-Hwee
authors.initials: SH
authors.lastname: Ng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D004149:Dioxoles; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D015363:Quinolones; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; CHM-1; GRP78; nasopharyngeal carcinoma; p85α