Title |
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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Published in |
BMC Cancer, December 2010
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DOI | 10.1186/1471-2407-10-672 |
Pubmed ID | |
Authors |
Mikhail G Dozmorov, Joseph T Azzarello, Jonathan D Wren, Kar-Ming Fung, Qing Yang, Jeffrey S Davis, Robert E Hurst, Daniel J Culkin, Trevor M Penning, Hsueh-Kung Lin |
Abstract |
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. 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. 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. 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. |
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Geographical breakdown
Country | Count | As % |
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United States | 1 | 2% |
Germany | 1 | 2% |
South Africa | 1 | 2% |
Unknown | 54 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Master | 10 | 18% |
Student > Bachelor | 8 | 14% |
Student > Ph. D. Student | 7 | 12% |
Researcher | 4 | 7% |
Student > Postgraduate | 4 | 7% |
Other | 16 | 28% |
Unknown | 8 | 14% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 17 | 30% |
Biochemistry, Genetics and Molecular Biology | 10 | 18% |
Medicine and Dentistry | 9 | 16% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 5% |
Unspecified | 2 | 4% |
Other | 6 | 11% |
Unknown | 10 | 18% |