title: Nicotinamide phosphoribosyltransferase can affect metastatic activity and cell adhesive functions by regulating integrins in breast cancer.
abstract: NAD(+) metabolism is an essential regulator of cellular redox reactions, energy pathways, and a substrate provider for NAD(+) consuming enzymes. We recently demonstrated that enhancement of NAD(+)/NADH levels in breast cancer cells with impaired mitochondrial NADH dehydrogenase activity, through augmentation of complex I or by supplementing tumor cell nutrients with NAD(+) precursors, inhibits tumorigenicity and metastasis. To more fully understand how aberrantly low NAD(+) levels promote tumor cell dissemination, we here asked whether inhibition of NAD(+) salvage pathway activity by reduction in nicotinamide phosphoribosyltransferase (NAMPT) expression can impact metastasis and tumor cell adhesive functions. We show that knockdown of NAMPT, the enzyme catalyzing the rate-limiting step of the NAD(+) salvage pathway, enhances metastatic aggressiveness in human breast cancer cells and involves modulation of integrin expression and function. Reduction in NAMPT expression is associated with upregulation of select adhesion receptors, particularly αvβ3 and β1 integrins, and results in increased breast cancer cell attachment to extracellular matrix proteins, a key function in tumor cell dissemination. Interestingly, NAMPT downregulation prompts expression of integrin αvβ3 in a high affinity conformation, known to promote tumor cell adhesive interactions during hematogenous metastasis. NAMPT has been selected as a therapeutic target for cancer therapy based on the essential functions of this enzyme in NAD(+) metabolism, cellular redox, DNA repair and energy pathways. Notably, our results indicate that incomplete inhibition of NAMPT, which impedes NAD(+) metabolism but does not kill a tumor cell can alter its phenotype to be more aggressive and metastatic. This phenomenon could promote cancer recurrence, even if NAMPT inhibition initially reduces tumor growth.
authors.affiliation: Departments of Chemical Physiology and Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: afsant@scripps.edu.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Santidrian
authors.affiliation: Departments of Chemical Physiology and Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: sleboeuf@scripps.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: LeBoeuf
authors.affiliation: Departments of Chemical Physiology and Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: wolde@scripps.edu.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Wold
authors.affiliation: Departments of Chemical Physiology and Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: melissa@scripps.edu.
authors.forename: Melissa
authors.initials: M
authors.lastname: Ritland
authors.affiliation: Departments of Chemical Physiology and Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: jsfrio@yahoo.com.
authors.forename: Jane S
authors.initials: JS
authors.lastname: Forsyth
authors.affiliation: Departments of Chemical Physiology and Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: brunie@scripps.edu.
authors.forename: Brunhilde H
authors.initials: BH
authors.lastname: Felding
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D016513:Mice, SCID; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D019096:Vitronectin; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Breast cancer; Integrins; Metastasis; NAD(+) salvage pathway; NAMPT; αvβ3