Tosylcyclonovobiocic acids promote cleavage of the hsp90-associated cochaperone p23.
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.
Radanyi
Christine
C
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
Le Bras
Gaëlle
G
Bouclier
Céline
C
Messaoudi
Samir
S
Peyrat
Jean-François
JF
Brion
Jean-Daniel
JD
Alami
Mouâd
M
Renoir
Jack-Michel
JM
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
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