Involvement of neutral endopeptidase in neoplastic progression
ABSTRACT Neutral endopeptidase 24.11 (NEP) is a 90-110 kDa cell surface cell surface peptidase that is normally expressed by numerous tissues, including prostate, kidney, intestine, endometrium, adrenal glands and lung. This enzyme cleaves peptide bonds on the amino side of hydrophobic amino acids and inactivates a variety of physiologically active peptides, including atrial natriuretic factor, substance P, bradykinin, oxytocin, Leu- and Met-enkephalins, neurotensin, bombesin, endothelin-1, and bombesin-like peptides. NEP reduces the local concentration of peptide available for receptor binding and signal transduction. Loss or decreases in NEP expression have been reported in a variety of malignancies. Reduced NEP may promote peptide-mediated proliferation by allowing accumulation of higher peptide concentrations at the cell surface, and facilitate the development or progression of neoplasia. We have used prostate cancer as model in which to study the involvement of NEP in malignancy. Using a variety of experimental approaches, including recombinant NEP, cell lines expressing wild-type and mutant NEP protein, and cell lines expressing NEP protein with a mutated cytoplasmic domain, we have examined the effects of NEP on cell migration and cell survival. We have shown that the effects of NEP are mediated by its ability to catalytically inactivate substrates such as bombesin and endothelin-1, but also through direct protein-protein interaction with other protein such as Lyn kinase [which associates with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) resulting in NEP-Lyn-PI3-K protein complex], ezrin/radixin/moesin (ERM) proteins, and the PTEN tumor suppressor protein. We review the mechanisms of NEP's tumor suppressive action and how NEP loss contributes to tumor progression.
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ABSTRACT: Neuroendocrine tumours (NETs) comprise a heterogenous group of malignancies with an often unpredictable course, and with limited treatment options. Thus, new diagnostic, prognostic, and therapeutic markers are needed. To shed new lights into the biology of NETs, we have by cDNA transcript profiling, sought to identify genes that are either up- or downregulated in NE as compared with non-NE tumour cells. A panel of six NET and four non-NET cell lines were examined, and out of 12 743 genes examined, we studied in detail the 200 most significantly differentially expressed genes in the comparison. In addition to potential new diagnostic markers (NEFM, CLDN4, PEROX2), the results point to genes that may be involved in the tumorigenesis (BEX1, TMEPAI, FOSL1, RAB32), and in the processes of invasion, progression and metastasis (MME, STAT3, DCBLD2) of NETs. Verification by real time qRT-PCR showed a high degree of consistency to the microarray results. Furthermore, the protein expression of some of the genes were examined. The results of our study has opened a window to new areas of research, by uncovering new candidate genes and proteins to be further investigated in the search for new prognostic, predictive, and therapeutic markers in NETs.British Journal of Cancer 10/2008; 99(8):1330-9. DOI:10.1038/sj.bjc.6604565 · 4.82 Impact Factor
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ABSTRACT: The involvement of peptidases in carcinogenetic processes of several tumor types has been researched in recent years. Although kidney is one of the major tissues known to express cystinyl-aminopeptidase (CAP), little is known about its role in renal neoplasia. This study analyzes fluorimetrically membrane-bound and soluble CAP activity in the three main renal cancers: clear cell (CCRCC), papillary (PRCC), and chromophobe (ChRCC) renal cell carcinomas. Overall, a marked decrease of membrane-bound CAP activity in all the three renal cell carcinomas was detected when compared with their respective surrounding non-tumor tissues. So, the tumor vs. non-tumor CAP ratios (units of peptidase per mg of protein) was as follows: 926+/-111 vs. 3778+/-276 for CCRCCs, 737+/-181 vs. 4351+/-950 for PRCCs, and 592+/-118 vs. 4905+/-935 for ChRCCs. In contrast, the soluble fraction of this enzyme displayed minor and non-significant changes when comparing tumor and non-tumor CAP activities in the whole series. After stratification by stage and grade, CCRCCs displayed significant differences: pT3 category had significantly higher levels of membrane-bound activity than pT1, and high grade cases (G3-4) had higher soluble CAP activity than low grade ones (G1-2). These data may open additional possibilities in the study of renal cell carcinoma with regard to the prognosis of patients.Regulatory Peptides 01/2008; 144(1-3):56-61. DOI:10.1016/j.regpep.2007.06.002 · 2.01 Impact Factor
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ABSTRACT: The endogenous opioids met- and leu-enkephalin are inactivated by peptidases preventing the activation of opioid receptors. Inhibition of enkephalin-degrading enzymes increases endogenous enkephalin levels and stimulates robust behavioral effects. RB101, an inhibitor of enkephalin-degrading enzymes, produces antinociceptive, antidepressant, and anxiolytic effects in rodents, without typical opioid-related negative side effects. Although enkephalins are not selective endogenous ligands, RB101 induces these behaviors through receptor-selective activity. The antinociceptive effects of RB101 are produced through either the mu-opioid receptor alone or through activation of both mu- and delta-opioid receptors; the antidepressant-like and anxiolytic effects of RB101 are mediated only through the delta-opioid receptor. Although little is known about the effects of RB101 on other physiologically and behaviorally relevant peptides, these findings suggest that RB101 and other inhibitors of enkephalin-degrading enzymes may have potential as novel therapeutic compounds for the treatment of pain, depression, and anxiety.CNS Drug Reviews 02/2007; 13(2):192-205. DOI:10.1111/j.1527-3458.2007.00011.x · 4.92 Impact Factor