Proteolysis of Complement Factors iC3b and C5 by the Serine Protease Prostate-Specific Antigen in Prostatic Fluid and Seminal Plasma

Abstract

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.

Context-dependent roles of complement in cancer

“…Sublytic complement C5b-9 protects prostate cancer cells from tumour necrosis factor-α-induced cell death 82 . Interestingly, proteolysis of iC3b and C5 by the serine protease prostate-specific antigen in prostatic fluid was detected, inhibiting the terminal pathway 83 .…”

Complement in cancer: untangling an intricate relationship

“…Of note, biochemical evaluation of this C3 cleavage fragment revealed a putative prostate-specific antigen (PSA) cleavage site. Indeed, purified PSA was able to cleave C3 and C5 in vitro , suggesting that PSA acts as an immunoregulatory protease that contributes to a pro-tumorigenic environment through the proteolysis of complement proteins 125 .…”

Age to End Dreadful Diseases (HIV, Malaria, TB, Cancer and More): A Theory of Intact or Protected Complement (IPC) Immunity

“…It could not be confirmed that PSA had a role in the pathogenesis of this disease until a C3 cleavage site was discovered by biochemical analysis with tryrosine-1348. Furthermore, purified PSA was able to cleave iC3b and the associated complement protein C5 [49]. These results revealed that PSA as an immune inhibition protease could assist to create a micro-environment beneficial to malignancy through degradation of the complement components.…”

“…A prostate-specific antigen (PSA) was found to continually express in high-level among the majority of men with both high-and low-grade prostate cancer [49]. It could not be confirmed that PSA had a role in the pathogenesis of this disease until a C3 cleavage site was discovered by biochemical analysis with tryrosine-1348.…”