title: Aromatic hydrocarbon receptor inhibits lysophosphatidic acid-induced vascular endothelial growth factor-A expression in PC-3 prostate cancer cells.
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.
authors.affiliation: Institute of Zoology, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Wu
authors.forename: Yueh-Chien
authors.initials: YC
authors.lastname: Lin
authors.forename: Shun-Yan
authors.initials: SY
authors.lastname: Lan
authors.forename: Yuan-Li
authors.initials: YL
authors.lastname: Huang
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000037:antagonists & inhibitors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000502:physiology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497396:ARNT protein, human; D043925:Angiogenesis Inducing Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; D018336:Receptors, Aryl Hydrocarbon; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C032881:lysophosphatidic acid
keywords: AHR; HIF-1; LPA; VEGF