The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Biomolecules. 2021 Nov 10;11(11):1666. doi: 10.3390/biom11111666.
A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate-aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation.
更好地理解肿瘤的代谢限制可能会导致更有效的抗癌治疗。近年来的证据表明，许多肿瘤类型对天冬氨酸有一个关键的依赖性。作为核苷酸合成的前体，天冬氨酸对细胞增殖是必不可少的。此外，苹果酸-天冬氨酸穿梭在氧化还原平衡中起着关键作用，天冬氨酸的缺乏会导致氧化应激。现在人们已经认识到，天冬氨酸的生物合成在很大程度上受线粒体代谢的控制，包括癌细胞中的呼吸作用和谷氨酰胺分解代谢。因此，在抑制线粒体代谢的条件下，包括突变、缺氧或化学抑制剂，天冬氨酸可能成为肿瘤生长和癌细胞存活的限制因素。值得注意的是，天冬氨酸的可用性与目前在临床或临床试验中的各种治疗方法的敏感性或耐药性有关，这表明迫切需要更有效的针对天冬氨酸的治疗方法。在这篇综述中，我们介绍了天冬氨酸在癌细胞中的代谢作用的最新知识，并描述了癌细胞在不同代谢状态下如何维持天冬氨酸水平。我们还强调了几种目前正在研究中的有前途的天冬氨酸水平调节剂。
