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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology*
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Blotting, Western
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Cell Hypoxia*
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Cell Movement
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Female
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Lysophospholipids / pharmacology*
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Mitogen-Activated Protein Kinases / metabolism
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Resveratrol
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Reverse Transcriptase Polymerase Chain Reaction
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Stilbenes / pharmacology*
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Transfection
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents, Phytogenic
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lysophospholipids
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RNA, Messenger
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Stilbenes
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Ribosomal Protein S6 Kinases, 70-kDa
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Mitogen-Activated Protein Kinases
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lysophosphatidic acid
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Resveratrol