title: Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma.
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-kappaB 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-kappaB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-kappaB pathway as a critical event in prostate tumorigenesis.
authors.affiliation: Spanish National Cancer Research Center, 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Fernandez-Marcos
authors.forename: Shadi
authors.initials: S
authors.lastname: Abu-Baker
authors.forename: Jayashree
authors.initials: J
authors.lastname: Joshi
authors.forename: Anita
authors.initials: A
authors.lastname: Galvez
authors.forename: Elias A
authors.initials: EA
authors.lastname: Castilla
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
authors.forename: Carmen
authors.initials: C
authors.lastname: Saez
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Jose
authors.initials: J
authors.lastname: Palacios
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011493:Protein Kinase C / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099221:Protein Kinase C zeta; C101296:prostate apoptosis response-4 protein; C494929:PTEN protein, human; C487757:Pten protein, mouse