Prostate-associated gene 4 (PAGE4) protects cells against stress by elevating p21 and suppressing reactive oxygen species production.
BACKGROUND
It is now widely recognized that there is a strong correlation between oxidative stress and the risk of benign and malignant diseases of the prostate. Prostate-associated gene 4 (PAGE4) is a Cancer/Testis Antigen (CTA) that was previously shown to be up-regulated in prostate cancer (PCa) and symptomatic as opposed to histologic benign prostatic hyperplasia (BPH). However, its functional role in these diseases is not fully understood.


METHODS
The mRNA level of PAGE4 was detected in isolated cell types in PCa tissues that were obtained from 8 men with PCa. PAGE4 protein expression profile was analyzed in a prostate disease tissue microarray. PAGE4 was overexpressed by pCMV-PAGE4-GFP transfection and cell viability was determined using the WST-1 assay.


RESULTS
PAGE4 expression is highly dynamic; while its expression is very high in fetal prostate it is drastically decreased in the normal adult prostate but is up-regulated both in symptomatic BPH and PCa. However, in the diseased prostate, PAGE4 is highly expressed in the epithelial cells of Proliferative Inflammatory Atrophy (PIA) lesions alluding to a potential stress response function of PAGE4. Consistent with such a role, PAGE4 protein levels are up-regulated when prostate cancer (PCa) cell lines are treated with various stress factors including the proinflammatory cytokine TNFα. Interestingly, in cells challenged with stress there is increased translocation of the PAGE4 protein to the mitochondrion and production of reactive oxygen species is suppressed . Furthermore, p21 is elevated in a p53-independent manner in PAGE4-overexpressing cells which results in impeded cell cycle progression, attenuated stress-induced DNA damage, and decreased cell death.


CONCLUSIONS
PAGE4 may be contributing to the development of PCa by playing a stress-protective and anti-apoptotic role.
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland ; Department of Urology, Institute of Urology, The First Hospital, China Medical University Shenyang, China.
Yu
Y
Zeng
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland.
Dong
D
Gao
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland ; Current address: University of California, Berkeley and University of California, San Francisco Graduate Program in Bioengineering USA.
John J
JJ
Kim
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland.
Takumi
T
Shiraishi
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland.
Naoki
N
Terada
Department of Urology, Kagawa University Faculty of Medicine Kita-gun, Kagawa, Japan.
Yoshiyuki
Y
Kakehi
Department of Urology, Institute of Urology, The First Hospital, China Medical University Shenyang, China.
Chuize
C
Kong
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland.
Robert H
RH
Getzenberg
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland ; Department of Oncology, The Johns Hopkins University School of Medicine Baltimore, Maryland.
Prakash
P
Kulkarni
Cancer/Testis Antigen; PAGE4; proliferative inf﻿l ammatory atrophy; prostate cancer; stress-response