title: NAMPT/PBEF1 enzymatic activity is indispensable for myeloma cell growth and osteoclast activity.
abstract: Multiple myeloma (MM) cells typically grow in focal lesions, stimulating osteoclasts that destroy bone and support MM. Osteoclasts and MM cells are hypermetabolic. The coenzyme nicotinamide adenine dinucleotide (NAD(+)) is not only essential for cellular metabolism; it also affects activity of NAD-dependent enzymes, such as PARP-1 and SIRT-1. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin, encoded by PBEF1) is a rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide. Coculture of primary MM cells with osteoclasts induced PBEF1 upregulation in both cell types. PBEF1 expression was higher in experimental myelomatous bones than in nonmyelomatous bone and higher in MM patients' plasma cells than in healthy donors' counterparts. APO866 is a specific PBEF1 inhibitor known to deplete cellular NAD(+). APO866 at low nanomolar concentrations inhibited growth of primary MM cells or MM cell lines cultured alone or cocultured with osteoclasts and induced apoptosis in these cells. PBEF1 activity and NAD(+) content were reduced in MM cells by APO866, resulting in lower activity of PARP-1 and SIRT-1. The inhibitory effect of APO866 on MM cell growth was abrogated by supplementation of extracellular NAD(+) or NAM. APO866 inhibited NF-κB activity in osteoclast precursors and suppressed osteoclast formation and activity. PBEF1 knockdown similarly inhibited MM cell growth and osteoclast formation. In the SCID-rab model, APO866 inhibited growth of primary MM and H929 cells and prevented bone disease. These findings indicate that MM cells and osteoclasts are highly sensitive to NAD(+) depletion and that PBEF1 inhibition represents a novel approach to target cellular metabolism and inhibit PARP-1 and bone disease in MM.
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors: Sathisha Upparahalli
authors: SU
authors: Venkateshaiah
authors: Sharmin
authors: S
authors: Khan
authors: Wen
authors: W
authors: Ling
authors: Rakesh
authors: R
authors: Bam
authors: Xin
authors: X
authors: Li
authors: Frits
authors: F
authors: van Rhee
authors: Saad
authors: S
authors: Usmani
authors: Bart
authors: B
authors: Barlogie
authors: Joshua
authors: J
authors: Epstein
authors: Shmuel
authors: S
authors: Yaccoby
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D009243:NAD / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009536:Niacinamide / Q000378:metabolism; D009537:Nicotinamide Mononucleotide / Q000031:analogs & derivatives / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010010:Osteoclasts / Q000201:enzymology* / Q000502:physiology; D010014:Osteolysis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011817:Rabbits; D056564:Sirtuin 1 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000178:Acrylamides; D016207:Cytokines; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010880:Piperidines; D009243:NAD; D009537:Nicotinamide Mononucleotide; D009536:Niacinamide; C002953:nicotinate mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C447939:SIRT1 protein, human; D056564:Sirtuin 1