Anti-angiogenic activity of PSA-derived peptides

Abstract

The interaction of a hydrophilic domain on the surface of the PSA molecule with a target on the cell membrane of prostate endothelial and epithelial cells was responsible for the anti-angiogenic or anti-tumorigenic activity of PSA: enzymatic activity was not associated with anti-angiogenic effects. Furthermore, since PSA and ACT are both expressed within the human prostate tissue microenvironment, the balance of their expression may represent a mechanism for endogenous regulation of tissue angiogenesis.

TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1

“…In particular we suggested that the activity of PSA on TRPM8 channels was not direct but mediated by bradykinin 2 receptor (Gkika et al, 2010) and therefore can act also on the ER form of the channel, which is the one present in ECs. Moreover, the antiangiogenic role of PSA has been reported by several groups in vitro and in vivo and is not dependent on its proteolytic activity (Fortier et al, 2003; Chadha et al, 2015). Collectively, our results reveal a new role for TRPM8 as a Rap1 inhibitor that arrests EC migration, whereas this effect could be regulated by PSA, an endogenous activator of the channel in vivo.…”

KLK3 in the Regulation of Angiogenesis—Tumorigenic or Not?

“…Since then, several studies have confirmed the antiangiogenic activity of KLK3 in the HUVEC tube formation model with sub-physiological KLK3 concentrations [30,54,55]. KLK3 has also been found to inhibit capillary-like sprouting of HUVECs grown on beads in fibrin gels [56].…”

“…The mechanism by which KLK3 exerts its antiangiogenic effect in these models is still unclear. Studies utilizing KLK3-isoforms with different proteolytic activity (like the inactive proform and internally cleaved KLK3 [54], and a less active KLK3-isoform with an amino acid change due to a polymorphism in the KLK3 gene [30]), KLK3-inhibitors [51,54,56,57] and -stimulators [58] all suggest that proteolytic activity of KLK3 is closely related to the antiangiogenic activity. However, some studies suggest that also a proteolytically inactive KLK3 retains antiangiogenic activity [53,59].…”

“…However, some studies suggest that also a proteolytically inactive KLK3 retains antiangiogenic activity [53,59]. It has also been described that 11-17 amino acid long peptides, representing the areas (on a linear sequence) that are predicted to be on the surface of KLK3 molecule and hypothesized to be capable of interacting with unknown cell surface targets, have the antiangiogenic activity [56]. It is somewhat difficult to understand why two separate linear peptides would have such an activity.…”

The role of prostate-specific antigen in the osteoblastic bone metastasis of prostate cancer: a literature review

“…Interestingly, Chadha et al. once reported an exception that PSA exhibited anti-angiogenic effects on human umbilical vein endothelial cells (HUVEC), and these effects were dependent on the regions outside the enzymatically active domains of PSA ( 77 ).…”