Mechanisms of apoptosis by the tumor suppressor Par-4

Abstract

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.

Figure 1. Functional domains of Par-4

Functionally active domains of Par-4 that are conserved across the human, rat and mouse species are depicted. The numbers depict their relative amino acid positions.

Figure 2. Putative domains of human Par-4

Putative domains of human Par-4 with functions yet to be confirmed experimentally are shown. Domains marked by ‡ are conserved across the human, mouse and rat species.

Figure 3. Relationship between mRNA levels of Par-4 and patient survival

(A) Oncomine anaylsis indicated increased Par-4 mRNA levels correlate with decreased survival in squamous cell lung carcinoma patients (logrank P = 0.061). Survival time in patients with lung adenocarcinoma shows no significant correlation with mRNA levels of Par-4 (logrank P = 0.94). (B) A composite of multiple data sets from Oncomine depicting 1 year survival status in patients with squamous cell carcinoma and adenocarcinoma of the lung. The colored squares represent data from different studies.