Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progressioan
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- 作者：Mikhail G Dozmorov (1)
Joseph T Azzarello (2) (3)
Jonathan D Wren (1)
Kar-Ming Fung (2) (4) (5)
Qing Yang (2)
Jeffrey S Davis (2)
Robert E Hurst (2) (6)
Daniel J Culkin (2)
Trevor M Penning (7)
Hsueh-Kung Lin (1) (3) (5) - 刊名：BMC Cancer
- 出版年：2010
- 出版时间：December 2010
- 年：2010
- 卷：10
- 期：1
- 全文大小：1489KB
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78. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/672/prepub - 作者单位：Mikhail G Dozmorov (1)
Joseph T Azzarello (2) (3)
Jonathan D Wren (1)
Kar-Ming Fung (2) (4) (5)
Qing Yang (2)
Jeffrey S Davis (2)
Robert E Hurst (2) (6)
Daniel J Culkin (2)
Trevor M Penning (7)
Hsueh-Kung Lin (1) (3) (5)
1. Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, 73104, Oklahoma City, Oklahoma, USA
2. Department of Urology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, USA
3. Department of Physiology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA
4. Department of Pathology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA
5. Oklahoma City Department of Veterans Affairs Medical Center, 73104, Oklahoma City, OK, USA
6. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA
7. Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA - ISSN：1471-2407
文摘
Background Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression. Methods To recapitulate elevated AKR1C3 expression in cancerous prostate, the human PCa PC-3 cell line was stably transfected with an AKR1C3 expression construct to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analysis were performed to identify AKR1C3-mediated pathways of activation and their potential biological consequences in PC-3 cells. Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and an in vitro Matrigel angiogenesis assays were applied to validate the pro-angiogenic activity of PC3-AKR1C3 transfectants identified by bioinformatics analysis. Results Microarray and bioinformatics analysis suggested that overexpression of AKR1C3 in PC-3 cells modulates estrogen and androgen metabolism, activates insulin-like growth factor (IGF)-1 and Akt signaling pathways, as well as promotes tumor angiogenesis and aggressiveness. Levels of IGF-1 receptor (IGF-1R) and Akt activation as well as vascular endothelial growth factor (VEGF) expression and secretion were significantly elevated in PC3-AKR1C3 transfectants in comparison to PC3-mock transfectants. PC3-AKR1C3 transfectants also promoted endothelial cell (EC) tube formation on Matrigel as compared to the AKR1C3-negative parental PC-3 cells and PC3-mock transfectants. Pre-treatment of PC3-AKR1C3 transfectants with a selective IGF-1R kinase inhibitor (AG1024) or a non-selective phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) abolished ability of the cells to promote EC tube formation. Conclusions Bioinformatics analysis followed by functional genomics demonstrated that AKR1C3 overexpression promotes angiogenesis and aggressiveness of PC-3 cells. These results also suggest that AKR1C3-mediated tumor angiogenesis is regulated by estrogen and androgen metabolism with subsequent IGF-1R and Akt activation followed by VEGF expression in PCa cells.