Department of Functional Genomics, Korea University of Science &Technology (UST), Daejeon, Korea.
Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Exp Mol Med. 2017 Jun 9;49(6):e344. doi: 10.1038/emm.2017.74.
Emerging evidence has emphasized the importance of cancer therapies targeting an abnormal metabolic state of tumor-initiating cells (TICs) in which they retain stem cell-like phenotypes and nicotinamide adenine dinucleotide (NAD) metabolism. However, the functional role of NAD metabolism in regulating the characteristics of TICs is not known. In this study, we provide evidence that the mitochondrial NAD levels affect the characteristics of glioma-driven SSEA1 TICs, including clonogenic growth potential. An increase in the mitochondrial NAD levels by the overexpression of the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT) significantly suppressed the sphere-forming ability and induced differentiation of TICs, suggesting a loss of the characteristics of TICs. In addition, increased SIRT3 activity and reduced lactate production, which are mainly observed in healthy and young cells, appeared following NNT-overexpressed TICs. Moreover, in vivo tumorigenic potential was substantially abolished by NNT overexpression. Conversely, the short interfering RNA-mediated knockdown of NNT facilitated the maintenance of TIC characteristics, as evidenced by the increased numbers of large tumor spheres and in vivo tumorigenic potential. Our results demonstrated that targeting the maintenance of healthy mitochondria with increased mitochondrial NAD levels and SIRT3 activity could be a promising strategy for abolishing the development of TICs as a new therapeutic approach to treating aging-associated tumors.
新出现的证据强调了针对肿瘤起始细胞（TIC）异常代谢状态的癌症治疗的重要性，在这种状态下，它们保持着类似干细胞的表型和烟酰胺腺嘌呤二核苷酸（NAD）代谢。然而，NAD 代谢在调节 TIC 特征方面的功能作用尚不清楚。在这项研究中，我们提供的证据表明，线粒体 NAD 水平影响了由神经胶质瘤驱动的 SSEA1 TIC 的特征，包括集落形成生长潜能。通过过度表达线粒体酶烟酰胺核苷酸转氢酶（NNT）增加线粒体 NAD 水平，显著抑制了 TIC 的球体形成能力并诱导其分化，表明 TIC 特征丧失。此外，在 NNT 过表达 TIC 中观察到主要在健康和年轻细胞中出现的 SIRT3 活性增加和乳酸生成减少。此外，NNT 过表达实质上消除了体内致瘤潜力。相反，通过短发夹 RNA 介导的 NNT 敲低促进了 TIC 特征的维持，这表现在大肿瘤球体数量增加和体内致瘤潜力增加。我们的研究结果表明，针对具有增加的线粒体 NAD 水平和 SIRT3 活性的健康线粒体的维持可能是一种很有前途的策略，可以消除 TIC 的发展，作为治疗与衰老相关的肿瘤的新治疗方法。
