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Submitted on December 21, 2005
Accepted on June 19, 2006
Department of Surgery and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710; Department of Pathology, Medical College of Georgia, Augusta, GA 30912
* To whom correspondence should be addressed. 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 (AR) activation, and we show that LPA1 transduces G
i-dependent signals to promote nuclear localization of AR 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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