Nicotera Thomas M, Schuster David P, Bourhim Mustapha, Chadha Kailash, Klaich Gary, Corral David A
Department of Cancer Prevention & Population Sciences, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Prostate. 2009 Sep 1;69(12):1270-80. doi: 10.1002/pros.20968.
Serum prostate specific antigen (PSA) levels in prostate cancer patients serve as a useful biomarker for diagnosing and monitoring prostate cancer. Recently, secreted PSA has been characterized as an autocrine survival factor through activation of Akt and induction of AR. In the normal prostate, PSA is secreted in the lumen of prostatic ducts to lyse proteins in the seminal coagulum.
However, the mechanism for constitutive PSA secretion from benign prostate and its transport across the prostate-blood barrier into serum are unknown. Regulation of peptide secretion by iPLA(2)-beta has been reported in non-prostatic tissue and in prostate tissue iPLA(2)-beta is reported to be under androgen regulation. We investigated whether iPLA(2) plays a role for in PSA secretion by comparing iPLA(2) activity and expression in normal prostate epithelial RWPE-1 cells and in LNCaP prostate cancer cells. Expression of the two active iPLA(2)-beta mRNA splice variants, LH-iPLA(2) and SH-iPLA(2), were increased and the inhibitory ankyrin-iPLA(2) isoform was markedly reduced in LNCaP cells as compared to normal prostate epithelial RWPE-1 cells.
These changes are consistent with a higher enzymatic activity in LNCaP cells. The iPLA(2)-beta-specific inhibitor BEL inhibited PSA secretion and induced apoptosis in LNCaP cells. iPLA(2) knockdown using SiRNA inhibited PSA secretion, downregulated AR and induced apoptosis. Exogenous PSA suppressed BEL-induced apoptosis and neutralizing anti-PSA antibody blocked the survival effect of PSA.
These data indicate that iPLA(2)-beta participates in regulating PSA secretion and supports the concept that secreted PSA provides an autocrine survival function in LNCaP cells.
前列腺癌患者的血清前列腺特异性抗原（PSA）水平是诊断和监测前列腺癌的有用生物标志物。最近，分泌型PSA已被表征为一种自分泌存活因子，可通过激活Akt和诱导AR发挥作用。在正常前列腺中，PSA分泌到前列腺导管腔中以溶解精囊中的蛋白质。
然而，良性前列腺中PSA组成性分泌及其穿过前列腺-血屏障进入血清的机制尚不清楚。在非前列腺组织中已报道iPLA(2)-β对肽分泌有调节作用，并且在前列腺组织中，iPLA(2)-β据报道受雄激素调节。我们通过比较正常前列腺上皮RWPE-1细胞和LNCaP前列腺癌细胞中iPLA(2)的活性和表达，研究了iPLA(2)是否在PSA分泌中起作用。与正常前列腺上皮RWPE-1细胞相比，LNCaP细胞中两种活性iPLA(2)-β mRNA剪接变体LH-iPLA(2)和SH-iPLA(2)的表达增加，而抑制性锚蛋白-iPLA(2)亚型明显减少。
这些变化与LNCaP细胞中较高的酶活性一致。iPLA(2)-β特异性抑制剂BEL抑制LNCaP细胞中的PSA分泌并诱导其凋亡。使用SiRNA敲低iPLA(2)可抑制PSA分泌，下调AR并诱导凋亡。外源性PSA抑制BEL诱导的凋亡，而中和性抗PSA抗体阻断PSA的存活效应。
这些数据表明iPLA(2)-β参与调节PSA分泌，并支持分泌型PSA在LNCaP细胞中提供自分泌存活功能的概念。
