Abstract
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.
Document Type
Article
Publication Date
1-9-2014
Digital Object Identifier (DOI)
http://dx.doi.org/10.1016/j.celrep.2013.12.020
Repository Citation
Burikhanov, Ravshan; Shrestha-Bhattarai, Tripti; Hebbar, Nikhil; Qiu, Shirley; Zhao, Yanming; Zambetti, Gerard P.; and Rangnekar, Vivek M., "Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4" (2014). Radiation Medicine Faculty Publications. 1.
https://uknowledge.uky.edu/radmed_facpub/1
Supplemental document 1
PIIS2211124713007651.mmc2.pdf (1859 kB)
Supplemental document 2
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Notes/Citation Information
Published in Cell Reports.
© 2014 The Authors All rights reserved.
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.