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  • However with regard to the involvement of PEP in

    2020-11-13

    However, with regard to the involvement of PEP in neoplastic processes, few studies and restricted to a very limited number of different tumors have been carried out [4], [18], [19]. Therefore, in order to ascertain the possible role of this enzyme in pathological proliferative tissues, in the present study we analyse the pattern of PEP activity in a large series of human neoplastic tissues.
    Materials and methods
    Results The activity of cytosolic and membrane-bound PEP in all the studied tumors is shown in Table 2A, Table 2B. Activity is expressed as pmol of product/min/mg protein (UP/mg protein) and reported as mean±standard error (SE). With the exception of chromophobe renal cell carcinoma (ChRCC), cytosolic PEP activity was higher in tumors than in their surrounding uninvolved tissues. These results were statistically significant in clear cell renal cell carcinoma (CCRCC), urothelial carcinoma of the renal pelvis (UCRP) and head and neck squamous cell carcinoma (HNSCC), where the activity increased 35%, 142% and 66% respectively (Table 2A and Fig. 1). In colorectal tumors, both cytosolic and membrane-bound PEP activity increased by more than 100% in adenomatous polyps (AP) with respect to adenocarcinomas (A) and normal intestinal mucosa (Table 2B). Although PEP activity was higher in carcinoma than in normal mucosa, this difference did not attain statistical significance.
    Discussion It has long been reported that expression and activity patterns of peptidases change in malignant tumors, suggesting their involvement in tumor cell growth, local invasion, and metastasis [13], [14]. Up and downregulation of the same peptidases in different tumors have supported the idea that tumor-growth regulation by these MK-8931 occurs in a tumor specific manner [13], [14], [22], [23], [24], [25], [26]. However, in the present study we found increased PEP activity in most of the analysed tumors, which was statistically significant in CCRCC, UCRP, HNSCC and colorectal AP. According to that observed in previous works in prostate, lung and thyroid tumors [4], [18], [19], these results could indicate a common mechanism of PEP in the regulation of different malignancies. Fibroblast Activation Protein (FAP), which is known to exhibit the same enzyme activity as PEP, is also upregulated in several tumors [27], [28]. Therefore it is conceivable that its activity could contribute to our results. However, FAP is an integral membrane-protein and we found the main differences in the cytosolic fraction. It is thus unlikely that FAP is the responsible for the changes found in this study. The high activity of the cytosolic PEP in developing tissues, its cellular localization around the nucleus and the inhibition of DNA synthesis by PEP inhibitors seems to involve this enzyme in cell proliferation and differentiation [11], [12], [29], [30], [31]. The present results reinforce this hypotheisis because the activity of the enzyme is higher in all the neoplasic tissue studied than in the surrounding normal tissue. However, the way in which a predominantly cytosolic enzyme takes part in the modulation of bioactive peptides or in other biological processes is under discussion [1], [2], [6]. Although secretion of PEP and other soluble peptidases into the extracellular space has been suggested as a possible peptide regulatory mechanism [2], [6], [32], [33], [34], [35], it is accumulating evidence in favor of intracellular trafficking and action of certain peptides and proteolytic enzymes, known as intracrine action [36], [37]. Thus, it has been suggested that a number of peptide substrates of PEP may act as intracrine factors in the intracellular space, inducing cell proliferation and angiogenesis in several tissues [38], [39]. On the other hand, it has been shown that PEP take part in regulating the concentration of intracellular inositol mediated by substance P, which binds intracellular neurokinin-I receptor [40], [41]. Also, it has been found that PEP is mainly localized in the perinuclear space associated with the microtubulin cytoeskeleton [42]. Therefore, the hypothesis of an increase of cytosolic PEP activity as cause or consequence of an intracellular peptide dysregulation or other intracellular events in tumor tissues should not be ruled out. Further studies will help to elucidate this topic.