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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / pharmacology*
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Animals
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Antineoplastic Agents / pharmacology*
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Autophagy / drug effects
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Autophagy / genetics
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Cell Line, Tumor
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Cell Survival
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Cytokines / antagonists & inhibitors*
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Cytokines / genetics
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Molecular Targeted Therapy
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism
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Multiprotein Complexes
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NAD / antagonists & inhibitors
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NAD / metabolism*
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
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Nicotinamide Phosphoribosyltransferase / genetics
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Nicotinamide Phosphoribosyltransferase / metabolism
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Organ Specificity
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Piperidines / pharmacology*
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Proteins / antagonists & inhibitors*
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Proteins / genetics
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Proteins / metabolism
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases
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Xenograft Model Antitumor Assays
Substances
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Acrylamides
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Antineoplastic Agents
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Cytokines
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Enzyme Inhibitors
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Multiprotein Complexes
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N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
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Piperidines
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Proteins
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RNA, Small Interfering
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NAD
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3