Carcinogenesis Advance Access originally published online on March 20, 2008
Carcinogenesis 2008 29(5):1077-1082; doi:10.1093/carcin/bgn069
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The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates
1 School of Pharmacy
2 Molecular and Environmental Toxicology Center, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA
* To whom correspondence should be addressed. Tel: +1 608 263 5453; Fax: +1 608 265 3316; Email: repeterson{at}pharmacy.wisc.edu
Hypoxia-inducible factor-1 alpha (HIF-1
) and aryl hydrocarbon receptor nuclear translocator (ARNT) are basic helix-loop-helix/per-arnt-sim (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 cultures, but not in Ahr+/+ cultures. However, vanadate induced upstream proteins in the phosphatidylinositol 3-kinase-signaling cascade to a similar extent in TRAMPs of each Ahr genotype, evidenced by v-akt murine thymoma viral oncogene homolog (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.
Abbreviations: AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; Akt, v-akt murine thymoma viral oncogene homolog; HIF-1, hypoxia-inducible factor-1 alpha; PI3K, phosphatidylinositol 3-kinase; TBST, tris-buffered saline tween-20; TRAMP, transgenic adenocarcinoma of the mouse prostate; VEGF, vascular endothelial growth factor
Received June 26, 2007; revised March 4, 2008; accepted March 8, 2008.