Selectivity toward cancer cells is the most desirable element in cancer therapeutics. Par-4 is a cancer cellselective 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.

Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of anti-apoptosis by NF-kappaB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum (ER) to the cell surface. Mechanistic investigations revealed that NF-kappaB mediated this anti-apoptotic mechanism by upregulating expression of UACA, a pro-inflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-kappaB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the ER to the cell surface. This pathway of anti-apoptosis could be inhibited by suppressing levels of NF-kappaB or UACA expression, which enhanced ER stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-kappaB through UACA elevation, which by attenuating ER stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.