Sangkop Febbie, Singh Geeta, Rodrigues Ely, Gold Elspeth, Bahn Andrew
Department of Anatomy, University of Otago, Dunedin, New Zealand.
Department of Physiology, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
Mol Cell Biochem. 2016 Mar;414(1-2):187-99. doi: 10.1007/s11010-016-2671-8. Epub 2016 Feb 24.
Elevated serum uric acid (SUA) or urate is associated with inflammation and gout. Recent evidence has linked urate to cancers, but little is known about urate effects in prostate cancer. Activins are inflammatory cytokines and negative growth regulators in the prostate. A hallmark of prostate cancer progression is activin insensitivity; however, mechanisms underlying this are unclear. We propose that elevated SUA is associated with prostate cancer counteracting the growth inhibitory effects of activins. The expression of activins A and B, urate transporter GLUT9 and tissue urate levels were examined in human prostate disease. Intracellular and secreted urate and GLUT9 expression were assessed in human prostate cancer cell lines. Furthermore, the effects of urate and probenecid, a known urate transport inhibitor, were determined in combination with activin A. Activin A expression was increased in low-grade prostate cancer, whereas activin B expression was reduced in high-grade prostate cancer. Intracellular urate levels decreased in all prostate pathologies, while GLUT9 expression decreased in benign prostatic hyperplasia, prostatitis and high-grade prostate cancer. Activin responsive LNCaP cells had higher intracellular and lower secreted urate levels than activin-insensitive PC3 cells. GLUT9 expression in prostate cancer cells was progressively lower than in prostate epithelial cells. Elevated extracellular urate was growth promoting in vitro, which was abolished by the gout medication probenecid, and it antagonized the growth inhibitory effects of activins. This study shows for the first time that a change in plasma or intracellular urate levels, possibly involving GLUT9 and a urate efflux transporter, has an impact on prostate cancer cell growth, and that lowering SUA levels in prostate cancer is likely to be therapeutically beneficial.
血清尿酸（SUA）或尿酸盐水平升高与炎症和痛风相关。最近有证据表明尿酸盐与癌症有关，但尿酸盐在前列腺癌中的作用知之甚少。激活素是前列腺中的炎症细胞因子和负生长调节因子。前列腺癌进展的一个标志是对激活素不敏感；然而，其潜在机制尚不清楚。我们提出，SUA升高与前列腺癌有关，可抵消激活素的生长抑制作用。在人类前列腺疾病中检测了激活素A和B、尿酸盐转运体GLUT9的表达以及组织尿酸盐水平。在人前列腺癌细胞系中评估了细胞内和分泌的尿酸盐及GLUT9的表达。此外，还确定了尿酸盐和已知的尿酸盐转运抑制剂丙磺舒与激活素A联合使用的效果。激活素A在低级别前列腺癌中表达增加，而激活素B在高级别前列腺癌中表达降低。在所有前列腺病变中细胞内尿酸盐水平均降低，而GLUT9在良性前列腺增生、前列腺炎和高级别前列腺癌中表达降低。与激活素不敏感的PC3细胞相比，激活素反应性LNCaP细胞具有更高的细胞内尿酸盐水平和更低的分泌尿酸盐水平。前列腺癌细胞中GLUT9的表达逐渐低于前列腺上皮细胞。细胞外尿酸盐升高在体外具有促生长作用，痛风药物丙磺舒可消除这种作用，并且它拮抗激活素的生长抑制作用。这项研究首次表明，血浆或细胞内尿酸盐水平的变化，可能涉及GLUT9和尿酸盐外排转运体，对前列腺癌细胞生长有影响，并且降低前列腺癌患者的SUA水平可能具有治疗益处。
