The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates.
Hypoxia-inducible factor-1 alpha (HIF-1alpha) 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-1alpha 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-1alpha, inducing expression of VEGF, a prerequisite for tumor growth and angiogenesis. Since ARNT is a common dimerization partner of AhR and HIF-1alpha, we hypothesized that the AhR inhibits prostate tumor formation by competing with HIF-1alpha 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-1alpha-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-1alpha 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.
Fritz
Wayne A
WA
School of Pharmacy,University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
Lin
Tien-Min
TM
Peterson
Richard E
RE
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000502:physiology; D019281:Dimerization; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000503:physiopathology / Q000517:prevention & control*; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014638:Vanadates / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D018336:Receptors, Aryl Hydrocarbon; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D014638:Vanadates