Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level
Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level
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DOI：
10.1111/cas.13886
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发表时间：
2019-02-01
期刊：
影响因子：
5.7
通讯作者：
Choi, Kwan Y.
中科院分区：
文献类型：
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作者：
Hong, Sun M.;Hwang, Sung W.;Choi, Kwan Y.
烟酰胺腺嘌呤二核苷酸（NAD）以氧化形式（NAD（+））和还原形式（NADH）存在。NAD（+）在癌症代谢中起着至关重要的作用，包括细胞信号传导，能量产生和氧化还原调节。然而，NAD（H）池大小（NAD（+）和NADH）是否可用作结肠癌进展的生物标志物仍不清楚。在这里，我们发现，由于烟酰胺磷酸核糖转移酶（NAMPT）介导的NAD（+）补救途径的激活，在结直肠癌（CRC）进展期间，NAD（H）池大小和NAD（+）/NADH比值均增加。NAMPT在结直肠癌患者的腺瘤和腺癌组织中表达上调。通过双光子激发荧光（TPEF）显微镜测量的NADH荧光强度在CRC细胞系、氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）诱导的CRC组织和来自CRC患者的肿瘤组织中一致地增加。NAD（H）库的增加抑制了过量活性氧（ROS）水平的积累，并且FK 866（NAMPT的特异性抑制剂）处理通过增加AOM/DSS小鼠中的ROS水平来减小CRC结节大小。总的来说，我们的结果表明NAMPT介导的NAD（H）库上调保护癌细胞免受有害的氧化应激，并且通过TPEF显微镜检测NADH荧光可能是监测CRC进展的潜在方法。
Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD(+)) and a reduced form (NADH). NAD(+) plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD(+) and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD(+)/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD(+) salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.