Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progressioan

BMC Cancer

Research Article

Mikhail G Dozmorov¹  Jonathan D Wren¹  Hsueh-Kung Lin²  Trevor M Penning³  Daniel J Culkin⁴  Qing Yang⁴  Jeffrey S Davis⁴  Robert E Hurst⁵  Kar-Ming Fung⁶  Joseph T Azzarello⁷ 

[1] Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, 73104, Oklahoma City, Oklahoma, USA;Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, 73104, Oklahoma City, Oklahoma, USA;Department of Physiology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Oklahoma City Department of Veterans Affairs Medical Center, 73104, Oklahoma City, OK, USA;Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA;Department of Urology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Department of Urology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Department of Urology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Department of Pathology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Oklahoma City Department of Veterans Affairs Medical Center, 73104, Oklahoma City, OK, USA;Department of Urology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;Department of Physiology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK, USA;

关键词: Vascular Endothelial Growth Factor;    Androgen Receptor;    Vascular Endothelial Growth Factor Expression;    LNCaP Cell;    Vascular Endothelial Growth Factor mRNA Expression;   

DOI  :  10.1186/1471-2407-10-672

 received in 2009-10-07, accepted in 2010-12-06,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundAldo-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.MethodsTo 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.ResultsMicroarray 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.ConclusionsBioinformatics 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.

【 授权许可】

Unknown   
© Dozmorov et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.