Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol

Soon Young Park, Kang Jin Jeong, Jangsoon Lee, Dae Sung Yoon, Wahn Soo Choi, Yong Kee Kim, Jeung Whan Han, Yoon Mee Kim, Bum Kyeong Kim, Hoi Young Lee
Cancer Letters 2007 December 8, 258 (1): 63-9
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.

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