Journal
CANCER LETTERS
Volume 258, Issue 1, Pages 63-69Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2007.08.011
Keywords
lysophosphatidic acid; resveratrol; hypoxia; HIF-1 alpha; VEGF; cell migration; ovarian cancer cells
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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-1 alpha and VEGF expression, as well as the effect of resveratrol on LPA and hypoxia-induced HIF-1 alpha and VEGF expression and human ovarian cancer cell migration. Our results show that LPA treatment under hypoxia increases HIF-1 alpha protein level, which leads to increased expression of VEGF protein and mRNA. These increases in HIF-1 alpha and VEGF expression are dramatically attenuated by resveratrol. The underlying mechanism of inhibition of HIF-1 alpha expression by resveratrol seems to be associated with both inactivation of p42/p44 MAPK and p70S6K, as well as enhanced degradation of HIF-1 alpha 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-1 alpha and VEGF, and that this enhancement is efficiently blocked by resveratrol. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
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