The differential sensitivity of Bcl-2-overexpressing human breast tumor cells to TRAIL or doxorubicin-induced apoptosis is dependent on Bcl-2 proteinlevels

Bcl-2 protein is a potent anti-apoptotic protein that inhibits a mitochondr ia-operated pathway of apoptosis in many cells. DNA damaging agents and dea th receptor ligands can activate this mitochondrial apoptotic mechanism. Tu mor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been sugg ested to escape from the inhibitory action of Bcl-2 protein. We show that i n human breast tumor MCF-7 cells, TRAIL induced a mitochondrial pathway of apoptosis that involved cytochrome c release from mitochondria and activati on of caspase 9. The DNA damaging drug doxorubicin also activated this mito chondria-regulated mechanism of apoptosis, which was inhibited in Bcl-2-ove rexpressing cells. We also demonstrate that in MCF-7 cells Bcl-2 might conf er resistance to TRAIL-induced apoptosis, depending on the expression level s of the anti-apoptotic protein. These results indicate that enhanced expre ssion of Bcl-2 in tumor cells can render these cells less sensitive not onl y to chemotherapeutic drugs but also to TRAIL.