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.
05/2012; 1(2):1-92. DOI:10.4199/C00056ED1V01Y201204NPE002
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ABSTRACT: Classical immunization methods do not generate catalytic antibodies (catabodies) but recent findings suggest that the innate antibody repertoire as a rich catabody source. We describe the specificity and amyloid β (Aβ) clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aβ C-terminus noncovalently and hydrolyzed Aβ rapidly, with no reactivity to the Aβ precursor protein, transthyretin amyloid aggregates or irrelevant proteins containing the catabody-sensitive Aβ dipeptide unit. The catabody dissolved preformed Aβ aggregates and inhibited Aβ aggregation more potently than an Aβ-binding IgG. Intravenous catabody treatment reduced brain Aβ deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Aβ hydrolysis appears to be an innate immune function that could be applied for therapeutic Aβ removal. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
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ABSTRACT: Background and Aims: Breast cancer is one of the leading causes of mortality in Indian women. Although breast cancer is an epithelial malignancy, stroma plays a key role in its development and pathogenesis. Stromal markers are now emerging as novel markers in assessing the prognosis of invasive breast cancer and have not been studied extensively till date. The aim of the present study is to study the stromal expression of CD10 in breast carcinoma, find its relationship with other prognostic markers and study the role stroma plays in breast cancer pathogenesis. Materials and Methods: A total of 70 cases of breast cancer were included in the study. Representative sections were taken and hematoxylin and eosin staining was done. Immunohistochemistry was performed with ER, PR, Her2neu and CD10. Stromal expression of CD10 (>10% stromal positivity was considered positive) in invasive breast carcinoma was noted and was statistically analyzed with different known prognostic markers of breast carcinoma. Results: Stromal expression of CD10 was found to be significantly associated with increasing tumor grade (P = 0.04), increasing mitotic rate (P = 0.33), worsening prognosis (P = 0.01), ER negativity (P = 0.0001), Her2neu positivity (P = 0.19) and with molecular subtypes (CD10 positivity with the HER2 type, and CD10 negativity with Luminal type). No correlation was found between CD10 overexpression and PR, age, menopausal status, tumor size, lymph node positivity and tumor stage. Conclusions: This study gives substantial proof to the various models/research papers explaining the role of stroma/CD10 in breast cancer pathogenesis. Keeping the role stroma plays in predicting prognosis and tumor response, CD10 should be included as a routine pre-chemotherapy marker in breast carcinoma. Further studies should be performed to see the role stroma plays in hormonal expression and the usefulness of CD10 to predict treatment failure in breast carcinomas receiving neoadjuvant therapy.Indian Journal of Pathology and Microbiology 10/2014; 57(4):530-536. DOI:10.4103/0377-4929.142639 · 0.64 Impact Factor