Proteolytic Activity of Prostate-Specific Antigen (PSA) towards Protein Substrates and Effect of Peptides Stimulating PSA Activity

Abstract

Prostate-specific antigen (PSA or kallikrein-related peptidase-3, KLK3) exerts chymotrypsin-like proteolytic activity. The main biological function of PSA is the liquefaction of the clot formed after ejaculation by cleavage of semenogelins I and II in seminal fluid. PSA also cleaves several other substrates, which may explain its putative functions in prostate cancer and its antiangiogenic activity. We compared the proteolytic efficiency of PSA towards several protein and peptide substrates and studied the effect of peptides stimulating the activity of PSA with these substrates. An endothelial cell tube formation model was used to analyze the effect of PSA-degraded protein fragments on angiogenesis. We showed that PSA degrades semenogelins I and II much more efficiently than other previously identified protein substrates, e.g., fibronectin, galectin-3 and IGFBP-3. We identified nidogen-1 as a new substrate for PSA. Peptides B2 and C4 that stimulate the activity of PSA towards small peptide substrates also enhanced the proteolytic activity of PSA towards protein substrates. Nidogen-1, galectin-3 or their fragments produced by PSA did not have any effect on endothelial cell tube formation. Although PSA cleaves several other protein substrates, in addition to semenogelins, the physiological importance of this activity remains speculative. The PSA levels in prostate are very high, but several other highly active proteases, such as hK2 and trypsin, are also expressed in the prostate and may cleave protein substrates that are weakly cleaved by PSA.

Unleashing the therapeutic potential of human kallikrein-related serine proteases

“…The upregulated processing of antimicrobial cathelicidin peptides such as LL-37 by KLK5 and KLK7 is implicated in acne rosacea 65 . protein (PTHRP) 114,115 . KLK3 activity mediates prostate cancer progression and metastasis, particularly to the bone 116 .…”

“…Prostate cancer cells can alter bone homeostasis by secreting KLK3, which influences bone formation by modifying the bone matrix or microenvironment. KLK3 targets tumour-promoting extracellular matrix (ECM) components (such as fibronectin, laminin, galectin 3 and nidogen 1), insulin-like-growth-factor-binding proteins (including IGFBP3 and IGFBP5) and parathyroid-hormone-related protein (PTHRP) 115,116 . By contrast, KLK4 mediates prostate cancer progression and androgen resistance by directly interacting with promyelocytic leukaemia zinc finger (PLZF) in prostate cancer tissues in vivo and inhibiting it from activating REDD1 (regulated in development and DNA damage response 1), relieving inhibition of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), thereby keeping mTOR signalling (and thus proliferation) uncontrollably active 125 Parkinson disease is characterized by the abnormal aggregation of insoluble α-synuclein 170 .…”

Kallikreins – The melting pot of activity and function

“…Recent reports, however, highlight the expression and mechanisms of action of other kallikreins in semen liquefaction, including proKLK3 (pro-PSA) activation by KLK-4, -5, -14, and -15, as well as the direct proteolytic activity of KLK-14 and -5 [100]. Following its activation, KLK3 degrades numerous proteins [extracellular matrix proteins, insulin-like growth factor (IGF)-binding proteins 3 and 5, and parathyroid-hormone-related protein (PTHRP)] facilitating metastasis of prostate cancer cells [65]. …”

Inhibitors of kallikrein‐related peptidases: An overview

“…This cation is thus considered as an important modulator of KLKs by reversibly binding into the active site. For example, it is well established that a reduction in the level of Zn 2+ in the prostate cancer tissue increases the KLK3 activity, suggesting the inhibitory action of Zn 2+ against this enzyme . The mechanism of inhibition of KLKs by Zn 2+ is generally noncompetitive.…”