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  • Tanespimycin Since the number of peptides hydrolized by PEP


    Since the number of peptides hydrolized by PEP is quite large, it is not easy to relate the increase of enzymatic activity with the altered changes of a concrete peptide. However, it is noticeable that imbalances of several natural substrates of PEP [6], such as angiotensins, bradykinin, vasopressin and thymosin-β4, lead to cell proliferation and tumor development [43], [44]. Therefore, the high levels of PEP activity observed in this study and in previous works [4], [18], [19] could lead to similar processes. Supporting this hypothesis, it has recently been described that a product of the conversion of thymosin-β4 by PEP, the angiogenic tetrapeptide acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) [45], is overexpressed in several neoplasms [19], [46] and is consistent with increases of PEP activity in thyroid carcinoma [19]. PEP activity has previously been demonstrated in human and rat urinary systems [4], [8], [47] and described as a urinary marker for renal injury [48]. Selective changes in the Tanespimycin and activity of several peptidases have been described in different kidney tumors and it has been suggested that this pattern could also be related to the histogenetic origin and/or agressiveness of the analysed tumors [23], [24], [25], [49], [50]. The present study, in support of these data, shows that PEP activity is increased in CCRCC, the most frequent renal cancer, which is thought to originate in the proximal nephron [51], and in urothelial carcinoma (UCRP). In contrast, ChRCC, another type of malignant renal cancer originating in the distal nephron [51], did not alter the PEP activity pattern. As observed in kidney tumors, cytosolic PEP activity also increased in HNSCC, the most frequent head and neck cancer [52]. Very recently we observed that aspartyl aminopeptidase activity, another cytosolic peptidase with angiotensinase activity, is also increased in this tumor [26]. These results are consistent with others describing similar changes in squamous cell lung carcinoma (SCLC), where the activity of PEP is significantly increased [18]. Although further studies are needed to determine the relevance of these initial results, more advanced studies have demonstrated that a soluble circulating form of aminopeptidase N/CD13 is related to the progression of this tumor [53] and proposed that bestatin, a potent APN/CD13 inhibitor, may be an effective drug for treating SCLC patients [54]. Another relevant result from the present work was obtained in the colorectal adenoma–adenocarcinoma sequence. This term describes the gradual progression from normal to dysplastic epithelium and on to carcinoma associated with the accumulation of genetic alterations [55]. It has long been reported that expression of several proteases, such as matrix metalloproteinases (MMPs) and peptidases, increases gradually throughout the sequence, playing an important role in the development and progression of these tumors [55], [56], [57], [58], [59]. Furthermore, some studies have suggested that the coordinated action of MMPs and peptidases, such as aminopeptidase N, dipeptidyl-peptidase IV and PEP, is important for the progression of several neoplastic and non-neoplastic chronic diseases [13], [14], [60], [61]. However, MMPs such as matrilysin-1 (MMP-7) are specially overexpressed in the early stages of the colorectal adenoma–adenocarcinoma pathway, with expression then stabilizing in cancerous lesions [62]. Our results pointed to a similar phenomenom: both cytosolic and membrane-bound PEP activities increased in malignant tumors (adenocarcinoma) when compared with the normal mucosa. However, highest activities were founded in precancerous lesions (adenomatous polyps). This activity pattern may indicate that PEP plays a role in the early phase of colorectal neoplastic development. In conclusion, this study analysed the activity pattern of PEP in a series of 122 solid tumors. The increased PEP activity in CCRCC, UCRP, HNSCC and colorectal AP suggests that this enzyme could be involved in these malignancies. As is the case of other diseases [1], [2], [6], Tanespimycin a better understanding of the pathophysiological role of PEP in proliferative disorders will be helpful for designing effective PEP inhibitors as therapeutic agents for neoplastic disease.