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Expression and Function of Lysophosphatidic Acid LPA₁ Receptor in Prostate Cancer Cells

Departments of Surgery (R.G., E.A.K., P.A., C.J.S., P.S., N.H.M., Y.D.) and Pharmacology and Cancer Biology (Y.D.), Duke University Medical Center, Durham, North Carolina 27710; and Department of Pathology (B.B., N.S., Y.D.), Medical College of Georgia, Augusta, Georgia 30912

Address all correspondence and requests for reprints to: Yehia Daaka, Department of Pathology, CN3114, Medical College of Georgia, Augusta, Georgia 30912. E-mail: ydaaka{at}mcg.edu.

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA₁, LPA₂, and LPA₃. We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA₁ gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA₁ gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA₁ and do not proliferate in response to LPA stimulation, implying LPA₁ transduces cell growth signals. Accordingly, stable expression of LPA₁ in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA₁ cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA₁ transduces Gi-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA₁ cells. These results suggest the possible utility of LPA₁ as a drug target to interfere with progression of prostate cancer.

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