Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
J Immunol. 2013 Mar 15;190(6):2567-74. doi: 10.4049/jimmunol.1200856. Epub 2013 Feb 11.
Prostate-specific Ag (PSA) is a serine protease that is expressed exclusively by normal and malignant prostate epithelial cells. The continued high-level expression of PSA by the majority of men with both high- and low-grade prostate cancer throughout the course of disease progression, even in the androgen-ablated state, suggests that PSA has a role in the pathogenesis of disease. Current experimental and clinical evidence suggests that chronic inflammation, regardless of the cause, may predispose men to prostate cancer. The responsibility of the immune system in immune surveillance and eventually tumor progression is well appreciated but not completely understood. In this study, we used a mass spectrometry-based evaluation of prostatic fluid obtained from diseased prostates after removal by radical prostatectomy to identify potential immunoregulatory proteins. This analysis revealed the presence of Igs and the complement system proteins C3, factor B, and clusterin. Verification of these findings by Western blot confirmed the high-level expression of C3 in the prostatic fluid and the presence of a previously uncharacterized C-terminal C3 cleavage product. Biochemical analysis of this C3 cleavage fragment revealed a putative PSA cleavage site after tyrosine-1348. Purified PSA was able to cleave iC3b and the related complement protein C5. These results suggest a previously uncharacterized function of PSA as an immunoregulatory protease that could help to create an environment hospitable to malignancy through proteolysis of the complement system.
前列腺特异性抗原（PSA）是一种丝氨酸蛋白酶，仅在正常和恶性前列腺上皮细胞中表达。大多数患有高级别和低级别前列腺癌的男性在疾病进展过程中，甚至在去雄激素状态下，PSA 的高水平表达持续存在，这表明 PSA 在疾病发病机制中起作用。目前的实验和临床证据表明，慢性炎症（无论其原因如何）可能使男性更容易患上前列腺癌。免疫系统在免疫监视和最终肿瘤进展中的作用得到了充分的认识，但尚未完全理解。在这项研究中，我们使用基于质谱的方法评估了根治性前列腺切除术后切除的患病前列腺中的前列腺液，以鉴定潜在的免疫调节蛋白。该分析显示存在 Ig 和补体系统蛋白 C3、因子 B 和簇蛋白。Western blot 对这些发现的验证证实了 C3 在前列腺液中的高水平表达以及存在以前未表征的 C 端 C3 切割产物。对该 C3 切割片段的生化分析揭示了在酪氨酸-1348 后存在潜在的 PSA 切割位点。纯化的 PSA 能够切割 iC3b 和相关的补体蛋白 C5。这些结果表明 PSA 具有以前未表征的免疫调节蛋白酶功能，通过对补体系统的蛋白水解作用，可能有助于创造有利于恶性肿瘤的环境。
