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[Cancer Research 66, 2740-2748, March 1, 2006]
© 2006 American Association for Cancer Research

Cell, Tumor, and Stem Cell Biology

Lysophosphatidic Acid Is a Major Regulator of Growth-Regulated Oncogene {alpha} in Ovarian Cancer

Zendra Lee1, Ramona F. Swaby2, Yuewei Liang1, Shuangxing Yu2, Shuying Liu2, Karen H. Lu3, Robert C. Bast, Jr.4, Gordon B. Mills2 and Xianjun Fang1

1 Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia and Departments of 2 Molecular Therapeutics, 3 Gynecological Oncology, and 4 Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xianjun Fang, Department of Biochemistry, Virginia Commonwealth University, PO Box 980614, Richmond, VA 23298. Phone: 804-828-0787; Fax: 804-828-1473; E-mail: xfang{at}vcu.edu.

Growth-regulated oncogene {alpha} (GRO{alpha}), a member of the chemokine superfamily, is commonly expressed in transformed cells and contributes to angiogenesis and tumorigenesis. Here, we report that increased GRO{alpha} levels are detected in the plasma and ascites of ovarian cancer patients. Ovarian cancer cell lines in culture express and secrete GRO{alpha}. However, when they are starved in serum-free medium, ovarian cancer cells ceased producing GRO{alpha}, suggesting that GRO{alpha} is not constitutively expressed but rather is produced in response to exogenous growth factors in ovarian cancer cells. The prototype peptide growth factors present in serum such as platelet-derived growth factor, insulin-like growth factor I, and insulin do not stimulate GRO{alpha} production by ovarian cancer cells. In contrast, lysophosphatidic acid (LPA), a glycerol backbone phospholipid mediator present in serum and ascites of ovarian cancer patients, is a potent inducer of GRO{alpha} expression in ovarian cancer cell lines. Treatment of ovarian cancer cells with LPA leads to transcriptional activation of the GRO{alpha} gene promoter and robust accumulation of GRO{alpha} protein in culture supernatants. The action of LPA on GRO{alpha} expression is mediated by LPA receptors, particularly the LPA2 receptor in that ectopic expression of these receptors restores the LPA-dependent GRO{alpha} production in nonresponsive cells. Down-regulation of LPA2 expression by small interfering RNA (siRNA) in ovarian cancer cells desensitizes GRO{alpha} production in response to LPA. The effect of serum on GRO{alpha} production is also significantly decreased by siRNA inhibition of LPA2 expression. These studies identify LPA as a primary regulator of GRO{alpha} expression in ovarian cancer. (Cancer Res 2006; 66(5): 2740-8)




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