Expression and function of lysophosphatidic acid LPA₁ receptor in prostate cancer cells

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 Gαi-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.