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Activation of Hypoxia-Inducible Factor-1 Is Necessary for Lysophosphatidic Acid–Induced Vascular Endothelial Growth Factor Expression

Authors' Affiliations: ¹ College of Medicine, Konyang University, Daejeon, Korea; ² College of Pharmacy, Sungkyunkwan University, Suwon, Korea; ³ Cancer Metastasis Research Center, College of Medicine, Yonsei University, Seoul, Korea; ⁴ College of Medicine, Kwandong University, Gangneung, Korea; and ⁵ Depatment of Molecular Cell and Developmental Biology, Mountain Sinai School of Medicine, New York, New York

Requests for reprints: Hoi Young Lee, Department of Pharmacology, College of Medicine, Konyang University, Daejeon, 302-718, Korea. Phone: 82-42-6006413; Fax: 82-42-5414626; E-mail: hoi{at}konyang.ac.kr.

Purpose: Lysophosphatidic acid (LPA) plays an important role in mediating cell proliferation, survival, and tumor invasion and angiogenesis. This bioactive phospholipid at the concentration in ascitic fluid stimulates the growth of malignant ovarian tumors by increasing the expression of vascular endothelial growth factor (VEGF). In the present study, we investigated whether LPA activates hypoxia inducible factor-1 (HIF-1), a key transcriptional complex in tumor progression and metastasis, thereby increasing the expression of VEGF.

Experimental Design: Immunoblotting, reverse transcription-PCR, ELISA, immunofluorescence, and chromatin immunoprecipitation assay were used to examine the expression of VEGF and HIF-1 in various cancer cells. Specific HIF-1 small interfering RNA was transfected to various cancer cells to determine the role of HIF-1 in LPA-induced VEGF expression.

Results: LPA induced expressions of VEGF and HIF-1 in OVCAR-3, CAOV-3, PC-3, and SK-Hep1 cells but not in SKOV-3 and Hep-3B cells. In OVCAR-3 and PC-3 cells, the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin/p70S6K and p42/p44 mitogen-activated protein kinase pathways were required for LPA-induced HIF-1 and VEGF expressions, whereas only the phosphoinositide 3-kinase/mammalian target of rapamycin/p70S6K pathway was important in SK-Hep1 cells. Immunofluorescence microscopy assay showed translocation of HIF-1 to nucleus by LPA, and chromatin immunoprecipitation assay revealed the binding of HIF-1 to the promoter of VEGF by LPA. Importantly, we found that small interfering RNA–induced reduction of HIF-1 expression significantly attenuated VEGF expression by LPA.

Conclusions: Our results show for the first time that LPA induces VEGF via HIF-1 activation and reveal a critical role of HIF-1 in LPA-induced cancer cell proliferation and angiogenesis.

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