Invited Speaker

A Paradigm for Cancer Selective Apoptosis
Vivek M. Rangnekar
USA

Prostate apoptosis response-4 (Par-4) is a pro-apoptotic protein with intracellular functions in the cytoplasm and nucleus. Previous studies have focused on the role of intracellular Par-4 in apoptosis of cancer cells. Interestingly, our recent studies suggest that Par-4 protein is spontaneously secreted by normal and cancer cells and that it produces both paracrine and autocrine effects selectively in cancer cells. Several agents that induce endoplasmic reticulum (ER) stress increase secretion of Par-4, and Par-4 secretion is not dependent on caspase activation or apoptosis. Extracellular Par-4 induces apoptosis by binding to a cell surface receptor in cancer cells. The interaction of extracellular Par-4 and the cell surface receptor leads to apoptosis via the extrinsic pathway involving caspase 8/caspase 3. Most importantly, Par-4 transports its own receptor to the cell surface and then extracellular Par-4 bindings to it to further amplify the ER stress pathway and apoptosis. Moreover, apoptosis inducible by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling. Our studies suggest that apoptosis is dependent on the coupled activation of endogenous and exogenous Par-4. Transgenic mice ubiquitously expressing Par-4 are resistant to the growth of spontaneous and inducible tumors. As Par-4 selectively induces apoptosis in cancer cells, not normal cells, it is an ideal candidate for cancer therapy.