Year of Publication
Doctor of Philosophy (PhD)
Toxicology and Cancer Biology
Dr. Vivek Rangnekar
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.
Shrestha Bhattarai, Tripti, "CROSS-TALK BETWEEN THE TUMOR SUPPRESSORS PAR-4 AND P53" (2015). Theses and Dissertations--Toxicology and Cancer Biology. 10.