title: Tosylcyclonovobiocic acids promote cleavage of the hsp90-associated cochaperone p23.
abstract: The cochaperone p23 is required for the chaperoning cycle of hsp90 and to enhance the maturation of several client proteins. Tosylcyclonovobiocic acids (4TCNA and 7TCNA) are potent analogs of novobiocin and induce cell cycle arrest, apoptosis and degradation of hsp90 client proteins in a panel of cancer cells. In this study, Western blotting shows that 4TCNA and 7TCNA triggered processing of the hsp90 cochaperone p23 in a dose-dependent manner. Small interfering RNA (siRNA)-mediated reduction of p23 expression in MCF-7 breast cancer cells did not block 4TCNA-induced caspase activation as assessed by the cleavage of PARP. This result indicates that 4TCNA-mediated cell death is a p23-independent process. In HT29 colon cancer cells, 4TCNA and 7TCNA up-regulated GRP78 and GRP94 supporting involvement of ER stress in apoptosis.
authors.affiliation: Université Paris Sud, CNRS, UMR 8612, Laboratoire de Pharmacologie Cellulaire et Moléculaire des Anticancéreux, Faculté de Pharmacie, IFR 141, 5 rue J.-B. Clément, F-92296 Châtenay-Malabry, France. christine.radanyi@u-psud.fr
authors.forename: Christine
authors.initials: C
authors.lastname: Radanyi
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Le Bras
authors.forename: Céline
authors.initials: C
authors.lastname: Bouclier
authors.forename: Samir
authors.initials: S
authors.lastname: Messaoudi
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Peyrat
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.forename: Mouâd
authors.initials: M
authors.lastname: Alami
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D024161:Collagen Type XI / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D047628:Estrogen Receptor alpha / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology*; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013312:Stress, Physiological; D015854:Up-Regulation
chemical_list: C535075:4-tosylcyclonovobiocic acid; C535076:7-tosylcyclonovobiocic acid; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D000091342:Endoplasmic Reticulum Chaperone BiP; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; C053387:endoplasmin; D009675:Novobiocin; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases