Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Prostate. 2012 Mar;72(4):399-409. doi: 10.1002/pros.21442. Epub 2011 Jun 16.
GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC), and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells, and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer.
We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role of GPRC6A in prostate cancer progression in vivo, we intercrossed Gprc6a(-/-) mice onto the TRAMP mouse prostate cancer model.
GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3, and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a(-/-) /TRAMP mice.
GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands.
GPRC6A 是一种营养感应 GPCR，在体外可被多种配体激活，包括氨基酸、钙、锌、骨钙素（OC）和睾酮。营养因素与前列腺癌风险之间的关联、OC 在前列腺癌细胞中表达增加的发现，以及 GPRC6A 与日本男性前列腺癌风险之间的关联提示 GPRC6A 在前列腺癌中发挥作用。
我们检查了 GPRC6A 是否在人前列腺癌细胞系中表达，并使用 siRNA 介导的 GPRC6A 表达敲低来探索 GPRC6A 在体外的功能。为了评估 GPRC6A 在体内前列腺癌进展中的作用，我们将 Gprc6a(-/-) 小鼠与 TRAMP 小鼠前列腺癌模型进行杂交。
与正常前列腺 RWPE-1 细胞系相比，GPRC6A 转录物在前列腺癌细胞系 22Rv1、PC-3 和 LNCaP 中显著增加。此外，一组 GPRC6A 配体，包括钙、OC 和精氨酸，在前列腺癌细胞系中表现出剂量依赖性地刺激 ERK 活性、细胞增殖、趋化性以及前列腺特异性抗原和 Runx2 基因表达。这些反应被 siRNA 介导的 GPRC6A 敲低所抑制。最后，将 Gprc6a 缺失转移到 TRAMP 前列腺癌模型上，显著延缓了前列腺癌的进展，并改善了复合 Gprc6a(-/-)/TRAMP 小鼠的存活率。
GPRC6A 是调节前列腺生长和癌症进展的新的分子靶点。GPRC6A 的增加可能增强前列腺癌细胞对膳食和骨源性配体增殖的能力。
