TY - JOUR
T1 - Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4
AU - Burikhanov, Ravshan
AU - Shrestha-Bhattarai, Tripti
AU - Hebbar, Nikhil
AU - Qiu, Shirley
AU - Zhao, Yanming
AU - Zambetti, Gerard P.
AU - Rangnekar, Vivek M.
N1 - Funding Information:
This study was supported by KLCR and NIH/NCI grant CA060872 (to V.M.R.).
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84895904920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84895904920&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.12.020
DO - 10.1016/j.celrep.2013.12.020
M3 - Article
C2 - 24412360
AN - SCOPUS:84895904920
SN - 2211-1247
VL - 6
SP - 271
EP - 277
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -
