Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

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Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

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Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation Shunsuke Okumura, MD, PhD, Takaaki Sasaki, MD, PhD, Yoshinori Minami, MD, Yoshinobu Ohsaki, MD, PhD Journal of Thoracic Oncology Volume 7, Issue 1, Pages 49-56 (January 2012) DOI: 10.1097/JTO.0b013e318233d686 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Non-small cell lung cancer (NSCLC) cells overexpress NAMPT-mRNA and NAMPT-specific siRNA suppresses proliferation of NSCLC. A, The expression of NAMPT-mRNA in NSCLCs was measured by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). NAMPT-expression levels were normalized to GAPDH-expression levels. The mean values were determined from three independent experiments. B, Cell proliferation was measured by BrdU assay on day 3 after siRNA transfection. The values were converted to a ratio in which each value in treated cells was compared with those in nontreated cells. The mean values were obtained from four independent experiments. Journal of Thoracic Oncology 2012 7, 49-56DOI: (10.1097/JTO.0b013e318233d686) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 FK866 suppresses proliferation of non-small cell lung cancer (NSCLC) cells. Cells were treated with the indicated concentrations of FK866 for 72 hours, and proliferation was measured by BrdU assay. The mean values were calculated from the three independent experiments. Journal of Thoracic Oncology 2012 7, 49-56DOI: (10.1097/JTO.0b013e318233d686) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Intracellular ATP levels decrease in FK866-treated non-small cell lung cancer (NSCLC). H1975 cells were treated with 1 nM or 10 nM FK866. ATP bioluminescence was assayed to measure ATP levels on the indicated times. The values are shown as a ratio (treated/nontreated). Journal of Thoracic Oncology 2012 7, 49-56DOI: (10.1097/JTO.0b013e318233d686) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 FK866 suppresses phosphorylation of EGFR-signal proteins in non-small cell lung cancer (NSCLC). A, H1975 cells were treated with or without 50 nM FK866 for the indicated periods. The expressions of p-EGFR and β-actin proteins at the indicated hours were assessed by WB. B, H1975 cells were treated with gefitinib or FK866 for 72 hours. The expression of EGFR-signal proteins was evaluated by WB. C, LC2, H1975, and PC9 cells were treated with the indicated concentrations of gefitinib or FK866. MEK1/2 and p-MEK1/2 expressions were assessed by WB. Journal of Thoracic Oncology 2012 7, 49-56DOI: (10.1097/JTO.0b013e318233d686) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 FK866 induces apoptosis of H1975 cells. H1975 cells were treated with 10 μM gefitinib or 50 nM FK866 for 72 hours. Apoptosis was visualized by FACS. A, Apoptosis was measured by PI-labeled cell counts (right), and the early phase of apoptosis was measured by annexin V-FITC signals (left). B, Numbers of apoptotic cells in treated cells. The values were converted to the percentage of apoptotic cells. The mean values were obtained from the three independent experiments. Journal of Thoracic Oncology 2012 7, 49-56DOI: (10.1097/JTO.0b013e318233d686) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 FK866 suppresses in vivo growth of H1975 tumors and inactivates ERK1/2 signals in the tumors. A, Nude mice were transplanted with H1975 cells and treated with 12.5 mg/kg gefitinib or 10 mg/kg FK866 on days 14 to 26. The graph shows tumor volumes measured. *p < 0.05. B, Immunohistochemistry shows the expression of p-ERK1/2 proteins in xenograft tumors (×40). Compared with the control (upper) and gefitinib (lower) groups, FK866 suppressed the expression of p-ERK1/2 in the tumor (middle). Journal of Thoracic Oncology 2012 7, 49-56DOI: (10.1097/JTO.0b013e318233d686) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions