Peroxiredoxin 2 in the nucleus and cytoplasm distinctly regulates androgen receptor activity in prostate cancer cells |
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Authors: | Shiota Masaki Yokomizo Akira Kashiwagi Eiji Takeuchi Ario Fujimoto Naohiro Uchiumi Takeshi Naito Seiji |
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Institution: | a Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japanb Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japanc Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan |
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Abstract: | Currently, few therapies are effective against castration-resistant prostate cancer. Increased activation of the androgen/androgen receptor (AR) signaling pathway is thought to promote castration-resistant prostate cancer. Herein, we report that peroxiredoxin (Prx) gene expression in castration-resistant prostate cancer and hydrogen peroxide-resistant cells was upregulated. Prx2 was overexpressed in castration-resistant prostate cancer at the mRNA and protein levels and was localized to the nucleus and cytoplasm. Overexpression of Prx2 increased AR transactivation, whereas Prx2 overexpression in the nucleus suppressed AR transactivation. These effects of Prx2 on AR activity were abolished by the introduction of function-disrupting mutations into Cys51 and Cys172. Silencing Prx2 reduced the expression of androgen-regulated genes and suppressed the growth of AR-expressing prostate cancer cells by inducing cell-cycle arrest at the G1 phase. Furthermore, Prx2 knockdown also suppressed cell growth in castration-resistant prostate cancer cells. These findings indicate that Prx2 is involved in the proliferation of AR-expressing prostate cancer cells by modulating AR activity. Designing therapeutics targeting Prx2 may offer a novel strategy for developing treatments for prostate cancer, including castration-resistant prostate cancer, which is dependent on AR signaling. |
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Keywords: | AR androgen receptor DHT dihydrotestosterone GAPDH glyceraldehyde-3-phosphate dehydrogenase NDRG1 N-Myc downstream regulated 1 NLS nuclear-localizing signal Prx peroxiredoxin PSA prostate-specific antigen SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis |
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