Effects of Manganese Superoxide Dismutase Silencing on Androgen Receptor Function and Gene Regulation: Implications for Castration-Resistant Prostate Cancer
Open Access
- 30 September 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 14 (19), 6073-6080
- https://doi.org/10.1158/1078-0432.ccr-08-0591
Abstract
Purpose: Advanced prostate cancer is first treated with androgen deprivation therapy. However, tumors become resistant to and grow despite castrate levels of testosterone. Growth and proliferation of CRPC is mediated by gain-of-function changes in the AR and AR reactivation. Expression of manganese superoxide dismutase (SOD2), which regulates cellular ROS, is markedly down-regulated in CRPC when compared with hormone-responsive tumors. Experimental Design: Here, we knocked down SOD2 expression in AR-expressing LNCaP prostate cancer cells and determined gene expression changes, transcription factor binding, and AR transcription activity in SOD2 knockdown cells. Results: SOD2 knockdown results in an increase in ROS. Gene expression changes induced by SOD2 knockdown results in the up-regulation of genes that are also androgen responsive and 46% of genes up-regulated 2-fold by the androgen ligand R1881 are also up-regulated to the same extent with SOD2 knockdown. The induction of many of these genes with SOD2 knockdown, such as VEGFA and FKBP5, is reversible with the antioxidant N-acetylcysteine, suggesting that this mechanism is directly linked to ROS. Furthermore, an array for transcription factor DNA-binding activity shows that SOD2 knockdown induces DNA binding by several transcription factors, including AR. SOD2 knockdown-induced AR activation was confirmed by electrophoretic mobility shift assay and luciferase activity, and both were readily reversible with N-acetylcysteine. Conclusions: These findings show that down-regulation of SOD2 induces AR activity in a ROS-dependent manner, and suggest that there may be a role for antioxidant therapy in CRPC.Keywords
This publication has 38 references indexed in Scilit:
- Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor GrowthCancer Research, 2008
- Advances in Male ContraceptionEndocrine Reviews, 2008
- HIF-Dependent Antitumorigenic Effect of Antioxidants In VivoCancer Cell, 2007
- Cell- and gene-specific regulation of primary target genes by the androgen receptorGenes & Development, 2007
- A Hierarchical Network of Transcription Factors Governs Androgen Receptor-Dependent Prostate Cancer GrowthMolecular Cell, 2007
- Integrated molecular profiling of SOD2 expression in multiple myelomaBlood, 2006
- Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancerProceedings of the National Academy of Sciences of the United States of America, 2006
- Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate CancerScience, 2005
- Androgen receptor signaling and vitamin D receptor action in prostate cancer cellsThe Prostate, 2005
- Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the ProstateJournal of Urology, 2002