title: Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4.
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.
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Tripti
authors.initials: T
authors.lastname: Shrestha-Bhattarai
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hebbar
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA; L.P. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: vmrang01@email.uky.edu.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019899:Paracrine Communication; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D018179:Receptors, Thrombin; D016159:Tumor Suppressor Protein p53; C422446:UACA antigen; C112908:protease-activated receptor 4