This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, K.-S. Articles by Xu, Y. Search for Related Content PubMed PubMed Citation Articles by Kim, K.-S. Articles by Xu, Y.

Hypoxia Enhances Lysophosphatidic Acid Responsiveness in Ovarian Cancer Cells and Lysophosphatidic Acid Induces Ovarian Tumor Metastasis In vivo

¹ Department of Cancer Biology, Lerner Research Institute, and ² Department of Obstetrics and Gynecology, Gynecological Oncology Section, Cleveland Clinic, Cleveland, Ohio; ³ Department of Obstetrics and Gynecology, Research Institute of Clinic Medicine, and ⁴ Department of Pharmacology, Chonbuk National University Medical School, Chonju, Chonbuk, Korea; ⁵ Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts; and ⁶ Department of Obstetrics and Gynecology, Indiana University, Indianapolis, Indiana

Requests for reprints: Yan Xu, Department of Obstetrics and Gynecology, Indiana University, 975 West Walnut Street, IB355A, Indianapolis, IN 46202. Phone: 317-274-3972; Fax: 317-278-2884; E-mail: xu2{at}iupui.edu.

Lysophosphatidic acid (LPA) is elevated in ascites of ovarian cancer patients and stimulates growth and other activities of ovarian cancer cells in vitro. Tissue hypoxia is a critical factor for tumor aggressiveness and metastasis in cancers. We tested whether the ascites of ovarian cancer is hypoxic and whether hypoxia influences the effects of LPA on ovarian cancer cells. We found that ovarian ascitic fluids were hypoxic in vivo. Enhanced cellular responsiveness to LPA, including migration and/or invasion of ovarian cancer cells, was observed under hypoxic conditions. This enhancement could be completely blocked by geldanamycin or a small interfering RNA targeting hypoxia-inducible factor 1 (HIF1). LPA-induced cell migration required cytosolic phospholipase A₂ (cPLA₂) and LPA stimulates cPLA₂ phosphorylation in a HIF1-dependent manner under hypoxia conditions. Furthermore, we show for the first time that exogenous LPA enhances tumor metastasis in an orthotopic ovarian cancer model and HIF expression in tumors. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (an inhibitor of the heat shock protein 90) effectively blocked LPA-induced tumor metastasis in vivo. Together, our data indicate that hypoxic conditions are likely to be pathologically important for ovarian cancer development. HIF1 plays a critical role in enhancing and/or sensitizing the role of LPA on cell migration and invasion under hypoxic conditions, where cPLA₂ is required for LPA-induced cell migration. (Cancer Res 2006; 66(16): 7983-90)

This article has been cited by other articles:

				H. Li, D. Wang, H. Zhang, K. Kirmani, Z. Zhao, R. Steinmetz, and Y. Xu Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice Mol. Cancer Ther., June 1, 2009; 8(6): 1692 - 1701. [Abstract] [Full Text] [PDF]

				Y. Song, J. Wu, R. A. Oyesanya, Z. Lee, A. Mukherjee, and X. Fang Sp-1 and c-Myc Mediate Lysophosphatidic Acid-Induced Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Cells via a Hypoxia-Inducible Factor-1-Independent Mechanism Clin. Cancer Res., January 15, 2009; 15(2): 492 - 501. [Abstract] [Full Text] [PDF]

				I. Woclawek-Potocka, J. Komiyama, J. S. Saulnier-Blache, E. Brzezicka, M. M. Bah, K. Okuda, and D. J Skarzynski Lysophosphatic acid modulates prostaglandin secretion in the bovine uterus Reproduction, January 1, 2009; 137(1): 95 - 105. [Abstract] [Full Text] [PDF]

				S. Yu, M. M. Murph, Y. Lu, S. Liu, H. S. Hall, J. Liu, C. Stephens, X. Fang, and G. B. Mills Lysophosphatidic Acid Receptors Determine Tumorigenicity and Aggressiveness of Ovarian Cancer Cells J Natl Cancer Inst, November 19, 2008; 100(22): 1630 - 1642. [Abstract] [Full Text] [PDF]

				S.-U. Chen, H. Lee, D.-Y. Chang, C.-H. Chou, C.-Y. Chang, K.-H. Chao, C.-W. Lin, and Y.-S. Yang Lysophosphatidic Acid Mediates Interleukin-8 Expression in Human Endometrial Stromal Cells through Its Receptor and Nuclear Factor-{kappa}B-Dependent Pathway: A Possible Role in Angiogenesis of Endometrium and Placenta Endocrinology, November 1, 2008; 149(11): 5888 - 5896. [Abstract] [Full Text] [PDF]

				P. S. Steeg, C. E. Horak, and K. D. Miller Clinical-Translational Approaches to the Nm23-H1 Metastasis Suppressor Clin. Cancer Res., August 15, 2008; 14(16): 5006 - 5012. [Abstract] [Full Text] [PDF]

				D. Wang, Z. Zhao, A. Caperell-Grant, G. Yang, S. C. Mok, J. Liu, R. M. Bigsby, and Y. Xu S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells Mol. Cancer Ther., July 1, 2008; 7(7): 1993 - 2002. [Abstract] [Full Text] [PDF]

				C. E. Horak, A. Mendoza, E. Vega-Valle, M. Albaugh, C. Graff-Cherry, W. G. McDermott, E. Hua, M. J. Merino, S. M. Steinberg, C. Khanna, et al. Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2 Cancer Res., December 15, 2007; 67(24): 11751 - 11759. [Abstract] [Full Text] [PDF]

				N. Said, M. J. Socha, J. J. Olearczyk, A. A. Elmarakby, J. D. Imig, and K. Motamed Normalization of the Ovarian Cancer Microenvironment by SPARC Mol. Cancer Res., October 1, 2007; 5(10): 1015 - 1030. [Abstract] [Full Text] [PDF]

				C. E. Horak, J. H. Lee, A. G. Elkahloun, M. Boissan, S. Dumont, T. K. Maga, S. Arnaud-Dabernat, D. Palmieri, W. G. Stetler-Stevenson, M.-L. Lacombe, et al. Nm23-H1 Suppresses Tumor Cell Motility by Down-regulating the Lysophosphatidic Acid Receptor EDG2 Cancer Res., August 1, 2007; 67(15): 7238 - 7246. [Abstract] [Full Text] [PDF]

				Z. Zhao, Y. Xiao, P. Elson, H. Tan, S. J. Plummer, M. Berk, P. P. Aung, I. C. Lavery, J. P. Achkar, L. Li, et al. Plasma Lysophosphatidylcholine Levels: Potential Biomarkers for Colorectal Cancer J. Clin. Oncol., July 1, 2007; 25(19): 2696 - 2701. [Abstract] [Full Text] [PDF]