Guo Rishu, Kasbohm Elizabeth A, Arora Puneeta, Sample Christopher J, Baban Babak, Sud Neetu, Sivashanmugam Perumal, Moniri Nader H, Daaka Yehia
Department of Surgery, Duke University of Medical Center, North Carolina 27710, USA.
Endocrinology. 2006 Oct;147(10):4883-92. doi: 10.1210/en.2005-1635. Epub 2006 Jun 29.
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 Galphai-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.
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蛋白偶联受体来促进细胞增殖、存活和迁移。我们分析了雄激素依赖性和雄激素不敏感前列腺癌细胞中LPA受体的基因表达，发现LPA(1)基因在雄激素不敏感且对LPA有反应的细胞中差异表达，而在雄激素依赖性且对LPA耐药的细胞中不表达。在人类前列腺标本中，与良性组织相比，LPA(1)基因在癌组织中的表达显著更高。雄激素依赖性的LNCaP细胞不表达LPA(1)，对LPA刺激也不增殖，这意味着LPA(1)可转导细胞生长信号。因此，LNCaP细胞中LPA(1)的稳定表达使其对LPA诱导的细胞增殖有反应，并缩短了它们在血清中的倍增时间。与野生型细胞形成的肿瘤相比，植入LNCaP-LPA(1)细胞导致动物肿瘤生长速度加快。LNCaP细胞的生长依赖于雄激素受体激活，我们发现LPA(1)可转导依赖Gαi的信号，促进雄激素受体的核定位和细胞增殖。此外，比卡鲁胺治疗可抑制LPA诱导的LNCaP-LPA(1)细胞的细胞周期进程和增殖。这些结果表明LPA(1)作为干扰前列腺癌进展的药物靶点具有潜在用途。
