文章：

NAD代谢组-癌细胞生物学的关键决定因素

The NAD metabolome — a key determinant of cancer cell biology

原文发布日期：2012-09-28

DOI: 10.1038/nrc3340

类型: Review Article

开放获取: 否

要点：

1. NAD is an important redox factor and substrate in various signalling processes, in which it is irreversibly degraded to form molecules that are of key relevance to cellular homeostasis. Both NAD⁺-dependent metabolic and signalling pathways are altered in cancer cells, providing a number of potential drug targets.
2. Permanent synthesis of NAD is essential to fuel bioenergetic processes and maintain balanced cell regulation. NAD⁺ is synthesized from vitamin B₃ (niacin, including both nicotinamide and nicotinic acid) and the corresponding nucleosides. However, the predominant source to maintain NAD levels is nicotinamide (Nam), which arises endogenously from NAD⁺-dependent signalling processes. Therefore, nicotinamide phosphoribosyltransferase (NamPRT) is of outstanding importance, as it is the only human enzyme that salvages Nam into NAD⁺ synthesis. NamPRT inhibitors are currently under scrutiny to evaluate their potential in cancer therapy based on NAD⁺ depletion.
3. Likewise, inhibitors of nicotinamide mononucleotide adenylyltransferases (NMNATs) have the potential to affect NAD levels, as these enzymes are required in all pathways of NAD⁺ generation. Moreover, the expression of the three human isoforms is tissue- and cell compartment-specific, suggesting the possibility of more specific therapeutic approaches. However, so far, specific and potent inhibitors are not available.
4. Several NAD-dependent signalling pathways are involved in the control of cell cycle progression, transcriptional regulation and DNA repair and have therefore been identified as promising targets in cancer therapy. The NAD⁺-dependent protein deacetylases (Sirtuins) SIRT1, SIRT3, SIRT6 and SIRT7 are also now of interest in the development of new cancer therapies.
5. Inhibitors of polyADP ribose polymerases (PARPs) have a demonstrated potential in cancer therapy and have recently reached the clinical arena. Major current challenges in their use are selectivity towards specific PARP isoforms, potential impairment of DNA repair in healthy tissues and development of drug resistance.

要点翻译：

1. NAD是一种重要的氧化还原因子，也是多种信号转导过程中的底物。在这些过程中，它会被不可逆地降解形成对细胞稳态至关重要的分子。癌细胞中依赖NAD+的代谢与信号通路均发生改变，这为药物研发提供了大量潜在靶点。
2. 持续合成NAD对于驱动生物能量过程和维持细胞调节平衡至关重要。NAD+由维生素B3（烟酸，包括烟酰胺和尼克酸）及其相应核苷合成。然而维持NAD水平的主要来源是内源性产生的烟酰胺，它源自NAD+依赖的信号转导过程。因此，烟酰胺磷酸核糖转移酶具有非凡重要性，它是人体内唯一能将烟酰胺重新纳入NAD+合成途径的酶。基于NAD+耗竭策略，目前正在深入研究NamPRT抑制剂在癌症治疗中的潜力。
3. 同样，烟酰胺单核苷酸腺苷酰转移酶抑制剂也可能影响NAD水平，因为所有NAD+生成途径都需要这些酶。此外，三种人类亚型的表达具有组织和细胞区室特异性，这为开发更具特异性的治疗方法提供了可能。但迄今为止仍缺乏高效特异的抑制剂。
4. 若干NAD依赖的信号通路参与细胞周期进程、转录调控和DNA修复的调控，因此已被确定为癌症治疗中有前景的靶点。目前NAD+依赖性蛋白去乙酰化酶家族中的SIRT1、SIRT3、SIRT6和SIRT7也已成为新型癌症疗法开发的关注焦点。
5. 聚ADP核糖聚合酶抑制剂在癌症治疗中已显示出明确潜力，并近期进入临床实践阶段。当前面临的主要挑战包括：对特定PARP亚型的选择性、对健康组织DNA修复功能的潜在影响以及耐药性的产生。

英文摘要：

NAD is a vital molecule in all organisms. It is a key component of both energy and signal transduction — processes that undergo crucial changes in cancer cells. NAD+-dependent signalling pathways are many and varied, and they regulate fundamental events such as transcription, DNA repair, cell cycle progression, apoptosis and metabolism. Many of these processes have been linked to cancer development. Given that NAD+-dependent signalling reactions involve the degradation of the molecule, permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. This necessity supports the targeting of NAD metabolism as a new therapeutic concept for cancer treatment.

摘要翻译： 

NAD是所有生物体中的重要分子。它是能量和信号转导的关键组成部分——这些过程在癌细胞中会发生关键性变化。NAD+依赖的信号通路多种多样，它们调控着转录、DNA修复、细胞周期进程、细胞凋亡和代谢等基本事件。这些过程中的许多都与癌症发展有关。鉴于NAD+依赖的信号反应涉及该分子的降解，通过不同生物合成途径进行的永久性核苷酸重新合成对于癌细胞持续增殖至关重要。这种需求支持将NAD代谢作为癌症治疗新靶向概念的观点。

原文链接：

The NAD metabolome — a key determinant of cancer cell biology