Open AccessSimultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma
Author(s) -
Pablo J. Fernández-Marcos,
Shadi Abu-Baker,
Jayashree Joshi,
Anita Gálvez,
Elias A. Castilla,
Marta Cañamero,
Manuel Collado,
Carmen Sáez,
Gema MorenoBueno,
José Palacios,
Michael Leitges,
Manuel Serrano,
Jorge Moscat,
Marı́a T. Diaz-Meco
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0813055106
Subject(s) - pten , tensin , prostate cancer , prostate , cancer research , loss of heterozygosity , carcinogenesis , biology , protein kinase b , tumor suppressor gene , pi3k/akt/mtor pathway , cancer , medicine , apoptosis , gene , genetics , allele
Prostate cancer is one of the most common neoplasias in men. The tumor suppressor Par-4 is an important negative regulator of the canonical NF-κB pathway and is highly expressed in prostate. Here we show that Par-4 expression is lost in a high percentage of human prostate carcinomas, and this occurs in association with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss. Par-4 null mice, similar to PTEN-heterozygous mice, only develop benign prostate lesions, but, importantly, concomitant Par-4 ablation and PTEN-heterozygosity lead to invasive prostate carcinoma in mice. This strong tumorigenic cooperation is anticipated in the preneoplastic prostate epithelium by an additive increase in Akt activation and a synergistic stimulation of NF-κB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-κB pathway as a critical event in prostate tumorigenesis.