RESUMO
Tumor necrosis factor (alpha)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (alpha) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor-induced apoptosis via the Bak pathway.
Assuntos
Carcinoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/deficiência , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/genéticaRESUMO
Apoptosis, the programmed cell death, is a highly regulated process, necessary for normal development and homeostasis of the functions of organisms. The Bcl-2 inhibitors BH3I-1 and BH3I-2 were used as lead compounds to find possible Bcl-2 or Bcl-X(L) inhibitors by using computer-assisted screening with our in-house database, containing more than four million commercially available molecules. Identified compounds were further investigated regarding their possible application as a drug.
