Stimulation of the mitogen-activated protein kinase pathway antagonizes TRAIL-induced apoptosis downstream of BID cleavage in human breast cancer MCF-7 cells.

We studied the role of the mitogen-activated protein kinase (MAPK) pathway in the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in breast tumor MCF-7 cells. We found that addition of a protein kinase C (PKC) activator to MCF-7 cultures prevented TRAIL-induced apoptosis, by inhibiting a step downstream of both caspase-8 activation and BID cleavage. TRAIL-induced translocation of Bax from cytosol to mitochondria, release of cytochrome c from mitochondria and activation of caspase-9 were all inhibited by PKC activation. PKC-mediated prevention of mitochondrial apoptotic events and apoptosis was found to be dependent on the MAPK pathway. Since TRAIL is a ligand of potential use in antineoplastic clinical trials, our findings may provide relevant information in cancer therapy.