Prolyl Endopeptidase Activity Is Correlated with Colorectal Cancer Prognosis

Abstract

Background and Objective: Prolyl endopeptidase (PEP) (EC 3.4.21.26) is a serine peptidase involved in differentiation, development and proliferation processes of several tissues. Recent studies have demonstrated the increased expression and activity of this cytosolic enzyme in colorectal cancer (CRC). However, there are no available data about the impact of this peptidase in the biological aggressiveness of this tumor in patient survival.Methods: The activity of PEP in tissue (n=80) and plasma (n=40) of patients with CRC was prospectively analyzed by fluorimetric methods. Results were correlated with the most important classic pathological data related to aggressiveness, with 5-year survival rates and other clinical variables.Results: 1) PEP is more active in early phases of CRC; 2) Lower levels of the enzyme in tumors were located in the rectum and this decrease could be related with preoperative chemo-radiotherapy; 3) PEP activity in tissue was higher in patients with better overall and disease-free survival (log-rank p<0.01, Cox analysis p<0.01); 4) Plasmatic PEP activity was significantly higher in CRC patients than in healthy individuals and this was associated with distant metastases and with worse overall and disease-free survivals (log-rank p<0.05, Cox analysis p<0.05).Conclusions: PEP activity in tissue and plasma from CRC patients is an independent prognostic factor in survival. The determination of PEP activity in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice.

Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

“…Our results show that tumor growth is suppressed in response to inhibition of FAP or POP proteolytic activity, thus intimating that these two proteinase functions are critical for tumor growth. With respect to POP, thymosin β4 peptides seem likely substrates, given the apparent role of their derivatives in angiogenesis [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] . Left open, however, is what substrate(s) might be involved, especially for cleavage by FAP, and this prompts conjectures about whether FAP cleavage of minimally degraded or denatured ECM proteins might yield peptides with unique biologic properties that might participate in pro-tumorigenic cell signaling, or whether FAP proteolytic function might be critical in pathways that promote immune tolerance of tumor growth, but if inhibited, immune intolerance is restored and growth becomes diminished.…”

“…POP is normally distributed throughout virtually all tissues, showing some increased expression in brain, kidney, and testes [59] . The distribution of POP within cells remains unsettled, although it is generally agreed that it is found mostly in cytosol [32] . It has been reported within the nucleus, and while lacking structural features consistent with membrane insertion, it is found on the external surface of cell membranes, conceivably through lipid conjugation [60] .…”

“…The relatively consistent findings of FAP, POP, and thymosin β4 overexpression in cancer TME has prompted efforts to determine whether inhibition of each or selected combinations might serve as a potential therapeutic target for tumor growth suppression [5] , [6] , [8] , [10] , [13] , [15] , [32] , [33] , [34] , [54] . Neither FAP nor POP has a precisely defined biologic function.…”

“…POP is believed to modulate the activities and levels of several biologic peptides < 30 amino acids, most of which lack clearly established functions [66] , [67] , [68] , [69] . Increased amounts of POP have been noted in cell cytosol and on cell membranes of cancers [30] , [31] , [32] . Tβ4, present in virtually all tissues, undergoes partial cleavage by an unidentified proteinase to generate fragments that POP—but not FAP—cleaves to yield several peptides, including the N-terminal tetrapeptide, acetyl-SDKP, which promotes angiogenesis at subnanomolar levels [33] , [38] , [61] .…”

“…Commanding less attention has been another prolyl oligopeptidase (POP) normally found in many tissues but commonly overexpressed along with the ubiquitous protein thymosin β4 in a number of malignancies [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] . Following partial cleavage of Tβ4 by an unknown enzyme, its degraded form is digested further by POP to yield the potent angiogenic peptide, Ac-SDKP [37] , [38] .…”