Lysophosphatidic Acid Is a Major Regulator of Growth-Regulated Oncogene α in Ovarian Cancer

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Abstract
Growth-regulated oncogene alpha (GROalpha), a member of the chemokine superfamily, is commonly expressed in transformed cells and contributes to angiogenesis and tumorigenesis. Here, we report that increased GROalpha levels are detected in the plasma and ascites of ovarian cancer patients. Ovarian cancer cell lines in culture express and secrete GROalpha. However, when they are starved in serum-free medium, ovarian cancer cells ceased producing GROalpha, suggesting that GROalpha 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 GROalpha 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 GROalpha expression in ovarian cancer cell lines. Treatment of ovarian cancer cells with LPA leads to transcriptional activation of the GROalpha gene promoter and robust accumulation of GROalpha protein in culture supernatants. The action of LPA on GROalpha expression is mediated by LPA receptors, particularly the LPA(2) receptor in that ectopic expression of these receptors restores the LPA-dependent GROalpha production in nonresponsive cells. Down-regulation of LPA(2) expression by small interfering RNA (siRNA) in ovarian cancer cells desensitizes GROalpha production in response to LPA. The effect of serum on GROalpha production is also significantly decreased by siRNA inhibition of LPA(2) expression. These studies identify LPA as a primary regulator of GROalpha expression in ovarian cancer.