title: Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition.
abstract: Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach.
authors.affiliation: LeBow Institute for Myeloma Therapeutics, Harvard Medical School, Boston, MA, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.forename: Antonia
authors.initials: A
authors.lastname: Cagnetta
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Aldo
authors.initials: A
authors.lastname: Roccaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Teresa
authors.initials: T
authors.lastname: Calimeri
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottini
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D009243:NAD / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D010880:Piperidines / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D011506:Proteins; D034741:RNA, Small Interfering; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3