Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis.
TRAP-1 is a mitochondrial heat shock protein (HSP), recently identified in Saos-2 osteosarcoma cells adapted to mild oxidative stress induced by diethylmaleate (DEM). TRAP-1 mRNA expression is increased in DEM-adapted cells as well as in tumor cells resistant to 5-fluorouracil and to platin derivatives. Since a strong decrease of TRAP-1 protein levels, upon cisplatin treatment, is observed only in controls but not in the DEM-adapted counterpart, a possible role for this protein in the development of resistant phenotypes could be hypothesized. To characterize the protective role of TRAP-1 against oxidative stress and apoptosis, stable transfectants were generated and characterized for their response to different stress types. These stable clones expressing constitutively high TRAP-1 levels: (i) are more resistant to H2O2-induced DNA damage and to apoptosis by cisplatin; (ii) contain higher reduced glutathione (GSH) levels than control cells; and (iii) do not release the apoptosis-inducing factor into the nucleus upon cisplatin treatment. Furthermore, high TRAP-1 levels interfere with caspase 3 activation. These results confirm the anti-apoptotic role of TRAP-1, and suggest that increased expression of this mitochondrial HSP in DEM-adapted and chemoresistant cells could be part of a pro-survival signaling pathway aimed to evade toxic effects of oxidants and anticancer drugs.
Montesano Gesualdi
N
N
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy.
Chirico
G
G
Pirozzi
G
G
Costantino
E
E
Landriscina
M
M
Esposito
F
F
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D020552:Comet Assay; D019008:Drug Resistance, Neoplasm; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D012516:Osteosarcoma / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C092306:TRAP1 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D006861:Hydrogen Peroxide; C022616:thiazolyl blue; D002945:Cisplatin