Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol.
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.
Park
Soon Young
SY
College of Medicine, Konyang University, Seo-Gu, Daejeon, Republic of Korea.
Jeong
Kang Jin
KJ
Lee
Jangsoon
J
Yoon
Dae Sung
DS
Choi
Wahn Soo
WS
Kim
Yong Kee
YK
Han
Jeung Whan
JW
Kim
Yoon Mee
YM
Kim
Bum Kyeong
BK
Lee
Hoi Young
HY
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
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