Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma.
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.
Fernandez-Marcos
Pablo J
PJ
Spanish National Cancer Research Center, 3 Melchor Fernandez Almagro Street, Madrid 28029, Spain.
Abu-Baker
Shadi
S
Joshi
Jayashree
J
Galvez
Anita
A
Castilla
Elias A
EA
Cañamero
Marta
M
Collado
Manuel
M
Saez
Carmen
C
Moreno-Bueno
Gema
G
Palacios
Jose
J
Leitges
Michael
M
Serrano
Manuel
M
Moscat
Jorge
J
Diaz-Meco
Maria T
MT
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
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