title: Nicotinamide phosphoribosyltransferase: a potent therapeutic target in non-small cell lung cancer with epidermal growth factor receptor-gene mutation.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC) often has an epidermal growth factor receptor (EGFR) gene mutation. Growth of EGFR-gene-mutated NSCLC depends predominantly on EGFR signaling and requires a large amount of intracellular ATP to activate EGFR signal transduction. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis, and it regulates intracellular ATP levels in mammalian cells. The effect of NAMPT inhibition on NSCLC has not been completely understood.
  
  
  METHODS
  We aimed to clarify the hypothesis that NAMPT inhibition suppresses growth of EGFR-gene-mutated NSCLC through reduction of intracellular ATP levels, using NAMPT-siRNA transfection and NAMPT inhibitor FK866. We used four lung adenocarcinoma cell lines, including H358 (Wild type EGFR), LC2 (EGFR), PC9 (EGFR), and H1975 (EGFR), and evaluated the effect of FK866 on these cells and its mechanisms, using cell proliferation, Western blot, ATP, and apoptosis assay.
  
  
  RESULTS
  We found that (1) H358, LC2, and H1975 cell lines highly expressed NAMPT-mRNA; (2) NAMPT-specific siRNA and FK866 suppressed proliferation of these NSCLCs; (3) FK866 reduced intracellular ATP levels in H1975 cells; (4) FK866 dephosphorylated EGFR signal proteins, including EGFR, Akt, Map kinase kinase 1/2, and extracellular signal-regulated kinase 1/2 (ERK 1/2); (5) FK866 induced apoptosis of H1975 cells; and (6) FK866 suppressed growth of H1975 xenograft tumors and attenuated expression of phospho-ERK 1/2 in the tumors in a tumor-bearing mouse model.
  
  
  CONCLUSIONS
  These findings indicate that NAMPT is a potent therapeutic target in the treatment of EGFR-gene-mutated NSCLC.
authors.affiliation: Respiratory Center, Asahikawa Medical University, Asahikawa, Hokkaido, Japan. okumura-@asahikawa-med.ac.jp
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Okumura
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Minami
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ohsaki
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D000178:Acrylamides; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; D054409:Nicotinamide Phosphoribosyltransferase; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2