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Nicotinamide Phosphoribosyltransferase Promotes Epithelial-to-Mesenchymal Transition as a Soluble Factor Independent of Its Enzymatic Activity

Soncini, D and Caffa, I and Zoppoli, G and Cea, M and Cagnetta, A and Passalacqua, M and Mastracci, L and Boero, S and Montecucco, F and Sociali, G and Lasiglie, D and Damonte, P and Grozio, A and Mannino, E and Poggi, A and D'Agostino, VG and Monacelli, F and Provenzani, A and Odetti, P and Ballestrero, A and Bruzzone, S and Nencioni, A (2014) Nicotinamide Phosphoribosyltransferase Promotes Epithelial-to-Mesenchymal Transition as a Soluble Factor Independent of Its Enzymatic Activity. Journal of Biological Chemistry . pp. 34189-34204.

Abstract

Boosting NAD(+) biosynthesis with NAD(+) intermediates has been proposed as a strategy for preventing and treating age-associated diseases, including cancer. However, concerns in this area were raised by observations that nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in mammalian NAD(+) biosynthesis, is frequently up-regulated in human malignancies, including breast cancer, suggesting possible protumorigenic effects for this protein. We addressed this issue by studying NAMPT expression and function in human breast cancer in vivo and in vitro. Our data indicate that high NAMPT levels are associated with aggressive pathological and molecular features, such as estrogen receptor negativity as well as HER2-enriched and basal-like PAM50 phenotypes. Consistent with these findings, we found that NAMPT overexpression in mammary epithelial cells induced epithelial-to-mesenchymal transition, a morphological and functional switch that confers cancer cells an increased metastatic potential. However, importantly, NAMPT-induced epithelial-to-mesenchymal transition was found to be independent of NAMPT enzymatic activity and of the NAMPT product nicotinamide mononucleotide. Instead, it was mediated by secreted NAMPT through its ability to activate the TGFbeta signaling pathway via increased TGFbeta1 production. These findings have implications for the design of therapeutic strategies exploiting NAD(+) biosynthesis via NAMPT in aging and cancer and also suggest the potential of anticancer agents designed to specifically neutralize extracellular NAMPT. Notably, because high levels of circulating NAMPT are found in obese and diabetic patients, our data could also explain the increased predisposition to cancer of these subjects

Item Type: Article
Additional Information: NIBR author: Cea, M institute: NIBR contributor address: From the Department of Internal MedicineFrom the Department of Internal Medicinethe Institut Jules Bordet, Universite Libre de Bruxelles, 1000 Brussels, Belgium, the Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892From the Department of Internal Medicine, the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139Department of Experimental Medicine, Section of Biochemistry, and Italian Institute of Biostructures and Biosystems, University of Genoa, 16132 Genoa, ItalyDepartment of Integrated Surgical and Diagnostic Sciences, Pathology Unit, University of Genoa, 16132 Genoa, Italy, the Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italythe Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, ItalyFrom the Department of Internal Medicine, the Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, andFrom the Department of Internal MedicineFrom the Department of Internal MedicineDepartment of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, andDepartment of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, andthe Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italythe Laboratory of Genomic Screening, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy, andFrom the Department of Internal Medicinethe Laboratory of Genomic Screening, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy, andFrom the Department of Internal Medicine, the Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, ItalyFrom the Department of Internal Medicine, the Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, andFrom the Department of Internal Medicine, the Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy, alessio.nencioni@unige.it
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/24940

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