Cancer-selective apoptotic effects of extracellular and intracellular Par-4

Abstract

Selectivity toward cancer cells is the most desirable element in cancer therapeutics. Par-4 is a cancer cell-selective proapoptotic protein that functions intracellularly in the cytoplasmic and nuclear compartments as a tumor suppressor. Moreover, recent findings indicate that the Par-4 protein is secreted by cells, and extracellular Par-4 induces cancer cell-specific apoptosis by interaction with the cell-surface receptor GRP78. This review describes the mechanisms underlying the apoptotic effects of both extracellular and intracellular Par-4 acting through its effector domain SAC.

Figure 1. Key intracellular and extracellular components of Par-4-mediated apoptosis

Intracellular Par-4 binds to aPKC in the cytoplasm to inhibit NF-κB activation and induce apoptosis. Moreover, various apoptotic stimuli trigger the nuclear translocation of Par-4 where, acting via its SAC domain, it inhibits NF-κB-mediated pro-survival signals, and promotes apoptosis. In the nucleus, Par-4 binds to topoisomerase I (TOPO-I) and sequesters it from the DNA to inhibit DNA relaxation and prevent cellular transformation. Intracellular Par-4 is also present in the ER, either as a complex with GRP78 or in an unbound state. ER-stress results in translocation of the GRP78-Par-4 complex to the plasma membrane. Secretion of Par-4 may occur following Par-4 dissociation from GRP78 either prior to its translocation to the cell surface (a), or after translocation to the cell surface (b). Alternately, intracellular Par-4 that is not bound to GRP78 may be secreted by a separate pathway, independent of GRP78 (c). Par-4, secreted in response to ER stress, binds to cell-surface GRP78 and amplifies the ER stress pathway to induce FADD/caspase-8-dependent apoptosis. This extrinsic pathway triggered by extracellular (secreted) Par-4 requires the function of intracellular Par-4 for translocation of GRP78 from the ER to the membrane. However, the role of nuclear translocation of intracellular Par-4 in the action of extracellular Par-4 is not clear.