Enzymatically active prostate‐specific antigen promotes growth of human prostate cancers

Williams, Simon A.; Jelinek, Christine; Litvinov, Ivan V.; Cotter, Robert J.; Isaacs, John T.; Denmeade, Samuel R.

doi:10.1002/pros.21375

Cited by 40 publications

(58 citation statements)

References 45 publications

(57 reference statements)

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“…In vivo, they found that low PSA expression and serum level is associated with lower tumor weight. In addition, they found that low PSA expression is associated with change in expression of many proteins which may indicate that PSA is part of regulatory mechanism of their expressions [40].…”

Section: The Effect Of Low Psamentioning

confidence: 99%

Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer

Altuwaijri¹

2012

JCT

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Prostate cancer (PCa) is most common diagnosed cancer in men and it is second most common cause of male cancer death. Many factors have been implicated in the pathogenesis of PCa. Although many papers have discussed the prostate specific antigen (PSA) as biomarker of PCa, very few have addressed its rule in the carcinogenesis, metastasis and invasion of PCa. In this article we will review the pathological role of PSA, as a potential target in the therapeutics of PCa.

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Section: The Effect Of Low Psamentioning

confidence: 99%

Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer

Altuwaijri¹

2012

JCT

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“…In-gel tryptic digestion was performed on all gel slices (1:20 ratio trypsin enzyme:substrate) for 18 h at 37°C. Mass spectrometric analysis and subsequent protein identifications were performed as described previously (4). …”

Section: Methodsmentioning

confidence: 99%

“…PSA is also produced in high amounts by prostate cancer cells. A role for PSA in the pathobiology of prostate cancer has been proposed based on its effect on prostate cancer growth (4) and its ability to cleave several important growth regulatory proteins (5). However, the exact role for PSA in prostate cancer has yet to be defined clearly.…”

mentioning

confidence: 99%

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

Manning

Williams

Jelinek

et al. 2013

The Journal of Immunology

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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.

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“…5 Prostate cancer cells disrupt this normal tissue architecture resulting in the leakage of increased amounts of PSA into the tissue interstitium and into the circulation, and it has been shown that enzymatically active PSA confers an enhanced growth rate to human prostate cancer cells, indicating a causal role in prostate cancer progression. 6 The PSA serum test is simple and inexpensive, and it has been a valuable tool in the detection, staging, and monitoring of prostate cancer. However, the PSA assay has always had a disadvantage in that it is not very specific, detecting common pathological conditions such as benign prostatic hyperplasia (BPH) and prostatitis.…”

Section: Introductionmentioning

confidence: 99%

Detection and quantification of enzymatically active prostate-specific antigenin vivo

Morin

Delaney

et al. 2013

J. Biomed. Opt

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Abstract. Assays for blood levels of prostate-specific antigen (PSA), performed in prostate cancer detection, measure mostly inactive/complexed PSA and do not provide information regarding enzymatically active PSA, which is biologically more relevant. Thus, we designed and synthesized an enzymatically cleavable peptide sequence labeled with near-infrared (NIR) fluorophores (ex/em 740∕770 nm) and coupled it to a pharmacokinetic modifier designed to improve its plasma kinetics. In its native state, the agent, PSA750 FAST™ (PSA750), is optically quenched (>95%) and only becomes fluorescent upon cleavage by active PSA, yielding a significant increase in signal. This activation is highly selective for PSA relative to a large panel of disease-relevant enzymes. Active PSA was detected in tumor frozen sections using PSA750 and this activity was abolished in the presence of the inhibitor, alpha-1 anti-chymotrypsin. In vivo imaging of tumor-bearing mice using fluorescence molecular tomography demonstrated a significantly higher fluorescent signal in PSA þ LNCaP tumors as compared to PSA − prostate cancer 3 tumors (13.0 AE 3.7 versus 2.8 AE 0.8 pmol, p ¼ 0.023). Ex vivo imaging of tumor sections confirms PSA750-derived NIR signal localization in nonvascular tissue. This is the first report that demonstrates the feasibility and effectiveness of noninvasive, real time, fluorescence molecular imaging of PSA enzymatic activity in prostate cancer. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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Enzymatically active prostate‐specific antigen promotes growth of human prostate cancers

Cited by 40 publications

References 45 publications

Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer

Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer

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

Detection and quantification of enzymatically active prostate-specific antigenin vivo

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