Aromatic hydrocarbon receptor inhibits lysophosphatidic acid-induced vascular endothelial growth factor-A expression in PC-3 prostate cancer cells
Journal
Biochemical and Biophysical Research Communications
Journal Volume
437
Journal Issue
3
Pages
440-445
Date Issued
2013
Author(s)
Abstract
Lysophosphatidic acid (LPA) is a lipid growth factor with multiple biological functions and has been shown to stimulate cancer cell secretion of vascular endothelial growth factor-A (VEGF-A) and trigger angiogenesis. Hypoxia-inducible factor-1 (HIF-1), a heterodimer consisting of HIF-1α and HIF-1β (also known as aromatic hydrocarbon receptor nuclear translocator (ARNT)) subunits, is an important regulator of angiogenesis in prostate cancer (PC) through the enhancement of VEGF-A expression. In this study, we first confirmed the ability of LPA to induce VEGF-A expression in PC-3 cells and then validated that LPA-induced VEGF-A expression was regulated by HIF-1α and ARNT through phosphatidylinositol 3-kinase activation. Aromatic hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with ARNT and was found to inhibit prostate carcinogenesis and vanadate-induced VEGF-A production. Since ARNT is a common dimerization partner of AHR and HIF-1α, we hypothesized that AHR might suppress LPA-induced VEGF-A expression in PC-3 cells by competing with HIF-1α for ARNT. Here we demonstrated that overexpression and ligand activation of AHR inhibited HIF-1-mediated VEGF-A induction by LPA treatment of PC-3 cells. In conclusion, our results suggested that AHR activation may inhibit LPA-induced VEGF-A expression in PC-3 cells by attenuating HIF-1α signaling, and subsequently, suppressing angiogenesis and metastasis of PC. These results suggested that AHR presents a potential therapeutic target for the prevention of PC metastasis. ? 2013 The Authors.
Subjects
AHR; HIF-1; LPA; VEGF
SDGs
Other Subjects
aromatic hydrocarbon receptor; lysophosphatidic acid; phosphatidylinositol 3 kinase; vanadic acid; vasculotropin A; article; cancer cell; carcinogenesis; controlled study; dimerization; enzyme activation; human; human cell; male; priority journal; prostate cancer; protein expression; AHR; HIF-1; LPA; VEGF; Angiogenesis Inducing Agents; Aryl Hydrocarbon Receptor Nuclear Translocator; Cell Line, Tumor; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lysophospholipids; Male; Neoplasm Metastasis; Neovascularization, Pathologic; Prostatic Neoplasms; Receptors, Aryl Hydrocarbon; Signal Transduction; Vascular Endothelial Growth Factor A
Type
journal article