CROSS-TALK BETWEEN THE TUMOR SUPPRESSORS PAR-4 AND P53

This work describes the fascinating interplay between two tumor suppressors Prostate apoptosis response-4 (Par-4) and p53. The guardian of the genome, p53, is frequently mutated in human cancers, and may contribute to therapeutic resistance. However, p53 is intact and functional in normal tissues, and we observed that specific activation of p53 in normal fibroblasts could induce apoptosis selectively in p53-deficient cancer cells. This paracrine apoptotic effect was executed by Par-4 secreted in response to p53 activation. Accordingly, activation of p53 in wild-type mice, but not in p53-/- or Par-4-/- mice, caused systemic elevation of Par-4 that induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of UACA, a binding partner of Par-4, and thereby releasing Par-4 from sequestration by UACA. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for inhibition of therapy-resistant tumors. Conversely, our studies have also revealed a definite role for Par-4 in regulating p53 expression. The pro-apoptotic tumor suppressor Par-4 is lost, down-regulated, inactivated or mutated in a number of cancers. Loss of Par-4 is associated with therapeutic resistance and poor disease prognosis, yet the mechanism for resistance is not clearly understood. Using genetically matched cells, we show that Par-4 expression is required for stabilization and function of the tumor suppressor p53, which constitutes the hub of signaling networks controlling important cellular and organismal phenotypes. In particular, the expression of p53 protein and its stabilization in response to genotoxic stress were remarkably attenuated in response to Par-4 loss. Accordingly, Par-4-null or -knockdown cells demonstrated increased resistance to apoptosis induced by genotoxic stress. Par-4 loss resulted in elevated Mdm2 activity, which is known to cause p53 degradation. Our findings suggest that Par-4 stabilizes p53 by inhibiting Akt-mediated phosphorylation of Mdm2 that is known to prevent translocation of Mdm2 into the nucleus for p53 ubiquitination and degradation. These studies identify a novel regulatory relationship between two tumor suppressors and may provide a better understanding of therapeutic resistance in tumors with p53 wild type status

Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4

The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53−/− or Par-4−/− mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity