Fritz Wayne A, Lin Tien-Min, Peterson Richard E
School of Pharmacy,University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
Carcinogenesis. 2008 May;29(5):1077-82. doi: 10.1093/carcin/bgn069. Epub 2008 Mar 20.
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.
缺氧诱导因子-1α（HIF-1α）和芳烃受体核转运蛋白（ARNT）是碱性螺旋-环-螺旋/Per-ARNT-Sim（PAS）家族转录因子。在血管生成和肿瘤生长过程中，HIF-1α与ARNT二聚化，诱导包括血管内皮生长因子（VEGF）在内的许多基因表达。ARNT也与芳烃受体（AhR）二聚化。AhR基因敲除（Ahr（-/-））的小鼠前列腺转基因腺癌（TRAMP）小鼠比AhR野生型（Ahr（+/+））TRAMP小鼠更易发生前列腺肿瘤，尽管前列腺上皮增生的发生率未受抑制。这表明AhR抑制前列腺癌发生。在TRAMP小鼠中，前列腺上皮增生导致HIF-1α稳定，诱导VEGF表达，这是肿瘤生长和血管生成的前提条件。由于ARNT是AhR和HIF-1α的共同二聚化伙伴，我们推测AhR通过与HIF-1α竞争ARNT来抑制前列腺肿瘤形成，从而限制VEGF产生。将Ahr（+/+）、Ahr（+/-）和Ahr（-/-）C57BL/6J TRAMP小鼠的前列腺在分级浓度的钒酸盐存在下培养，钒酸盐是通过HIF-1α-ARNT途径诱导VEGF的诱导剂。钒酸盐在Ahr（+/-）和Ahr（-/-）TRAMP培养物中以剂量依赖性方式诱导VEGF蛋白，但在Ahr（+/+）培养物中不诱导。然而，钒酸盐在每种Ahr基因型的TRAMP中以相似程度诱导磷脂酰肌醇3-激酶信号级联中的上游蛋白，这通过v-akt小鼠胸腺瘤病毒癌基因同源物（Akt）磷酸化得以证明。这些发现表明AhR隔离ARNT，减少与HIF-1α的相互作用，降低VEGF产生。由于VEGF是肿瘤血管化和生长所必需的，这些研究进一步表明VEGF的减少与Ahr（+/+）TRAMP小鼠中前列腺癌发生的抑制相关。
