Carcinogenesis Advance Access published online on March 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn069
The Aryl Hydrocarbon Receptor (AhR) Inhibits Vanadate-Induced Vascular Endothelial Growth Factor (VEGF) Production in TRAMP Prostates
,1
* School of Pharmacy and
Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI, USA 53705
1 To whom correspondence should be addressed at the School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705. Phone: (608) 263-5453. FAX: (608) 265-3316. E-mail: repeterson{at}pharmacy.wisc.edu
Hypoxia inducible factor-1
(HIF-1) and aryl hydrocarbon receptor nuclear translocator (ARNT) are PAS family transcription factors. During angiogenesis and tumor growth, HIF-1 dimerizes with ARNT, inducing expression of many genes, including vascular endothelial growth factor (VEGF). ARNT also dimerizes with the aryl hydrocarbon receptor (AhR). AhR null (Ahr-/-) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice develop prostate tumors with greater frequency than AhR wild-type (Ahr+/+) TRAMP mice, even though prevalence of prostate epithelial hyperplasia is not inhibited. This suggests that Ahr inhibits prostate carcinogenesis. In TRAMP mice, prostatic epithelial hyperplasia results in stabilized HIF-1, inducing expression of VEGF, a prerequisite for tumor growth and angiogenesis. Since ARNT is a common dimerization partner of AhR and HIF-1, we hypothesized that the AhR inhibits prostate tumor formation by competing with HIF-1 for ARNT, thereby limiting VEGF production. Prostates from Ahr+/+, Ahr+/- and Ahr-/- C57BL/6J TRAMP mice were cultured in the presence of graded concentrations of vanadate, an inducer of VEGF through the HIF-1/ARNT pathway. Vanadate induced VEGF protein in a dose-dependent fashion in Ahr+/- and Ahr-/- TRAMP prostate cultures, but not in Ahr+/+ cultures. However, vanadate induced upstream proteins in the phosphatidylinositol 3-kinase signaling cascade to a similar extent in TRAMP prostates of each Ahr genotype, evidenced by Akt phosphorylation. These findings suggest that AhR sequesters ARNT, decreasing interaction with HIF-1 reducing VEGF production. Since VEGF is required for tumor vascularization and growth, these studies further suggest that reduction in VEGF correlates with inhibited prostate carcinogenesis in Ahr+/+ TRAMP mice.
Key Words: Aryl Hydrocarbon Receptor • TRAMP • PI3 Kinase • VEGF • HIF-1
Received June 26, 2007; revised March 4, 2008; accepted March 8, 2008.