RESUMO
The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is undergoing clinical trials as an antitumor drug. We show here that treatment of human breast cancer cells with 17DMAG facilitates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Down-regulation of receptor interacting protein (RIP1) is observed upon 17DMAG treatment concomitantly with inhibition of IkappaBalpha phosphorylation. Interestingly, RNAi-mediated knockdown of RIP1 expression is sufficient to sensitize human breast tumor cells to TRAIL-induced apoptosis through a NF-kappaB-independent, mitochondria-operated pathway. Our results indicate that RIP1 is important in maintaining resistance to TRAIL-induced apoptosis in breast tumor cells and highlight the potential therapeutic benefit of the combination of Hsp90 inhibitors and TRAIL against breast tumor cells.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Neoplasias da Mama/patologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo , Ativação Enzimática , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Inibidor de NF-kappaB alfa , Fosforilação , Interferência de RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , TransfecçãoRESUMO
The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is currently undergoing clinical trials as an antitumor drug. We show here that treatment of human multiple myeloma (MM) cells with 17DMAG induces mTOR inhibition and microtubule-associated protein light chain 3 (LC3) conversion (LC3-I to LC3-II), an indicator of autophagy. Interestingly, 17DMAG synergistically induces apoptosis through a mitochondria-operated pathway in the presence of the autophagy inhibitor 3-methyladenine (3-MA). Inhibition of autophagy by 3-MA facilitated caspase activation, cytochrome c release from mitochondria and poly (ADP-ribose) polymerase (PARP) cleavage in myeloma cells treated with 17DMAG. The potential use of Hsp90 and autophagy inhibitors combinations as a therapeutic tool in MM is further discussed in our work.