Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma

doi:10.1073/pnas.0813055106

Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma

^aSpanish National Cancer Research Center, 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain;
^bDepartment of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267;
^cUniversity Hospital “Virgen del Rocio,” Manuel Siurot Street, Seville 41013, Spain; and
^dThe Biotechnology Centre of Oslo, University of Oslo, N-0317, Oslo, Norway

Edited by Tak Wah Mak, Ontario Cancer Institute, Toronto, Canada, and approved April 23, 2009
↵¹P.J.F.-M. and S.A.-B. contributed equally to this work. (received for review December 22, 2008)

Abstract

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.

Footnotes

²To whom correspondence should be addressed. E-mail: maria.diazmeco{at}uc.edu
Edited by Tak Wah Mak, Ontario Cancer Institute, Toronto, Canada, and approved April 23, 2009
Author contributions: M.S., J.M., and M.T.D.-M. designed research; P.J.F.-M., S.A.-B., J.J., A.G., E.A.C., M. Cañamero, M. Collado, C.S., G.M.-B., and J.P. performed research; P.J.F.-M. and M.L. contributed new reagents/analytic tools; M.S., J.M., and M.T.D.-M. analyzed data; and M.S., J.M., and M.T.D.-M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0813055106/DCSupplemental.