Mechanisms of apoptosis by the tumor suppressor Par-4

Par‐4 is a pro‐apoptotic, tumor suppressor protein that induces apoptosis selectively in cancer cells. Endoplasmic reticulum‐stress and higher levels of protein kinase A in tumor cells confer the coveted feature of cancer selective response to extracellular and intracellular Par‐4, respectively. Recent studies have shown that systemic Par‐4 confers resistance to tumor growth in mice, and that tumor‐resistance is transferable by bone‐marrow transplantation. Moreover, recombinant Par‐4 inhibits the growth of tumors in mice. As systemic Par‐4 induces apoptosis via cell surface GRP78, strategies that promote GRP78 trafficking to the cell surface are expected sensitize cancer cells to circulating levels of Par‐4. This review illustrates the domains and mechanisms by which Par‐4 orchestrates the apoptotic process in both cell culture models and in physiological settings. J. Cell. Physiol. 227: 3715–3721, 2012. © 2012 Wiley Periodicals, Inc.