title: Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol.
abstract: Lysophosphatidic acid (LPA) is a bioactive phospholipid that is involved in various cellular events, including tumor invasion and metastasis. In the present study, we investigated the effects of LPA and hypoxia on HIF-1alpha and VEGF expression, as well as the effect of resveratrol on LPA and hypoxia-induced HIF-1alpha and VEGF expression and human ovarian cancer cell migration. Our results show that LPA treatment under hypoxia increases HIF-1alpha protein level, which leads to increased expression of VEGF protein and mRNA. These increases in HIF-1alpha and VEGF expression are dramatically attenuated by resveratrol. The underlying mechanism of inhibition of HIF-1alpha expression by resveratrol seems to be associated with both inactivation of p42/p44 MAPK and p70S6K, as well as enhanced degradation of HIF-1alpha protein, resulting in profound decrease in VEGF expression and cell migration. Collectively, these results show that LPA under hypoxic condition enhances cell migration through the sequential induction of HIF-1alpha and VEGF, and that this enhancement is efficiently blocked by resveratrol.
authors.affiliation: College of Medicine, Konyang University, Seo-Gu, Daejeon, Republic of Korea.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Park
authors.forename: Kang Jin
authors.initials: KJ
authors.lastname: Jeong
authors.forename: Jangsoon
authors.initials: J
authors.lastname: Lee
authors.forename: Dae Sung
authors.initials: DS
authors.lastname: Yoon
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
authors.forename: Jeung Whan
authors.initials: JW
authors.lastname: Han
authors.forename: Yoon Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Bum Kyeong
authors.initials: BK
authors.lastname: Kim
authors.forename: Hoi Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; D012333:RNA, Messenger; D013267:Stilbenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; C032881:lysophosphatidic acid; D000077185:Resveratrol