title: Nicotinamide phosphoribosyltransferase promotes epithelial-to-mesenchymal transition as a soluble factor independent of its enzymatic activity.
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 TGFβ signaling pathway via increased TGFβ1 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.
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Debora
authors.initials: D
authors.lastname: Soncini
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.affiliation: the Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium, the Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zoppoli
authors.affiliation: From 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 02139.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139.
authors.forename: Antonia
authors.initials: A
authors.lastname: Cagnetta
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Italian Institute of Biostructures and Biosystems, University of Genoa, 16132 Genoa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.affiliation: Department 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, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.affiliation: 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.
authors.forename: Silvia
authors.initials: S
authors.lastname: Boero
authors.affiliation: From the Department of Internal Medicine, the Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, and.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sociali
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Denise
authors.initials: D
authors.lastname: Lasigliè
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Damonte
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, and.
authors.forename: Alessia
authors.initials: A
authors.lastname: Grozio
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Mannino
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: the Laboratory of Genomic Screening, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy, and.
authors.forename: Vito G
authors.initials: VG
authors.lastname: D'Agostino
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Monacelli
authors.affiliation: the Laboratory of Genomic Screening, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy, and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Provenzani
authors.affiliation: From 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.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Odetti
authors.affiliation: From 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, and.
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.affiliation: From 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.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009243:NAD / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D009243:NAD; D009363:Neoplasm Proteins; D054409:Nicotinamide Phosphoribosyltransferase; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D053773:Transforming Growth Factor beta1; C508960:TGFB1 protein, human; C085455:nicotinamide phosphoribosyltransferase, human; C508053:ERBB2 protein, human
keywords: Breast Cancer; Epithelial-Mesenchymal Transition (EMT); Nicotinamide Adenine Dinucleotide (NAD); Secretion; Signaling