Yu Zeng1, Dong Gao2, John J Kim3, Takumi Shiraishi2, Naoki Terada2, Yoshiyuki Kakehi4, Chuize Kong5, Robert H Getzenberg2, Prakash Kulkarni6. 1. 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. 2. Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine Baltimore, Maryland. 3. 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. 4. Department of Urology, Kagawa University Faculty of Medicine Kita-gun, Kagawa, Japan. 5. Department of Urology, Institute of Urology, The First Hospital, China Medical University Shenyang, China. 6. 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.
Abstract
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.
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.
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