Expression and function of lysophosphatidic acid LPA1 receptor in prostate cancer cells
Expression and function of lysophosphatidic acid LPA1 receptor in prostate cancer cells
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DOI：
10.1210/en.2005-1635
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发表时间：
2006-10-01
期刊：
影响因子：
4.8
通讯作者：
Daaka, Yehia
中科院分区：
文献类型：
--
作者：
Guo, Rishu;Kasbohm, Elizabeth A.;Daaka, Yehia
生物活性磷脂溶血磷脂酸（LPA）通过作用于名为LPA（1）、LPA（2）和LPA（3）的同源G蛋白偶联受体，促进细胞增殖、存活和迁移。我们分析了LPA受体在雄激素依赖性和雄激素不敏感性前列腺癌细胞中的基因表达，发现LPA（1）基因在雄激素不敏感和LPA反应性细胞中差异表达，而在雄激素依赖性和LPA耐药细胞中无差异表达。在人前列腺标本中，LPA（1）基因在癌组织中的表达显著高于良性组织。雄激素依赖性LNCaP细胞不表达LPA（1），并且不响应于LPA刺激而增殖，这意味着LPA（1）转导细胞生长信号。因此，LPA（1）在LNCaP细胞中的稳定表达使它们对LPA诱导的细胞增殖产生响应，并降低它们在血清中的倍增时间。与野生型细胞形成的肿瘤相比，LNCaP-LPA（1）细胞的植入导致动物肿瘤生长速率增加。LNCaP细胞的生长依赖于雄激素受体的激活，我们发现LPA（1）转导G α i依赖性信号以促进雄激素受体的核定位和细胞增殖。此外，比卡鲁胺处理抑制LPA诱导的LNCaP-LPA（1）细胞的细胞周期进展和增殖。这些结果表明LPA（1）作为药物靶点干扰前列腺癌进展的可能效用。
The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA(1), LPA(2), and LPA(3). We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA(1) gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA(1) gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA(1) and do not proliferate in response to LPA stimulation, implying LPA(1) transduces cell growth signals. Accordingly, stable expression of LPA(1) in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA(1) 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 LPA(1) transduces G alpha i-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-LPA(1) cells. These results suggest the possible utility of LPA(1) as a drug target to interfere with progression of prostate cancer.