Targeting the dependency of cancer cells on the sirtuin SIRT5

由于癌症的异质性和癌症的多样性，新的抗癌药物的需求仍然很大。 对现有药物产生抗药性。这个由三个PI(Richard Cerione， Hning Lin和Robert Weiss)的目标是将抑制SIRT5作为治疗癌症的新策略。SIRT5是一个 Sirtuin家族的成员，已知具有NAD依赖的蛋白质赖氨酸脱酰作用 活动。它们在生理学中发挥着重要作用，包括转录、代谢和 寿命。我们是第一个发现SIRT5，一种具有很弱脱乙酰活性的线粒体sirtuin， 更喜欢水解带负电荷的酰基赖氨酸修饰，如琥珀酰基和丙二酸基赖氨酸， 蛋白质。我们和其他人已经确定赖氨酸琥珀酸化是一种丰富的翻译后修饰 这会影响许多代谢酶。此外，我们最近获得了令人振奋的初步数据，表明 SIRT5缺失损害小鼠肿瘤的发生和转移。在细胞水平上，我们发现 失活SIRT5抑制癌细胞的非锚定生长，但在某些情况下几乎没有作用 在常规单层培养中对增殖的影响。我们假设SIRT5介导的调控 新陈代谢是癌变和获得像锚定这样的属性所必需的- 独立增长和侵入性。拟议研究的一个目标是了解详细的 SIRT5在癌细胞以及肿瘤微环境中的分子功能。成功完成 这一目标的实现可能会阐明癌症对代谢变化的独特依赖性，知识 这有助于开发治疗癌症的新疗法。基于这部小说的发现 SIRT5的酶活性，我们已经开发出SIRT5的小分子抑制剂，它们具有非常高的选择性和 不要抑制其他sirtuins。一些抑制剂在细胞培养和细胞培养中显示出良好的抗癌活性 老鼠模型。这项提议的另一个目标是开发更多的SIRT5抑制剂，并在体内进行改进 在小鼠模型上的抗癌效果。我们对这本书强大的翻译潜力感到非常兴奋 该项目基于对酶的活性和生物化学的深入了解。 SIRT5，再加上对培养细胞和小鼠的严格生物学分析。

New anticancer agents are still in great demand due to the heterogeneous nature of cancer and the development of resistance to existing drugs. This collaborative proposal by three PIs (Richard Cerione, Hening Lin, and Robert Weiss) aims to establish SIRT5 inhibition as new strategy to treat cancers. SIRT5 is a member of the sirtuin family of enzymes that are known to have NAD+-dependent protein lysine deacylation activities. They play important roles in physiology, including the regulation of transcription, metabolism, and lifespan. We were the first to discover that SIRT5, a mitochondrial sirtuin with very weak deacetylation activity, prefers to hydrolyze negatively charged acyl lysine modifications, such as succinyl and malonyl lysine, from proteins. We and others have established lysine succinylation as an abundant post-translational modification that affects many metabolic enzymes. Moreover, we have recently obtained exciting preliminary data showing that SIRT5 deletion impairs tumorigenesis and metastasis in mice. At the cellular level, we found that inactivating SIRT5 inhibits the anchorage-independent growth of cancer cells, but in some cases has little effect on proliferation in conventional monolayer cultures. We hypothesize that SIRT5-mediated regulation of metabolism is required for malignant transformation and the acquisition of properties like anchorage- independent growth and invasiveness. One objective of the proposed studies is to understand the detailed molecular functions of SIRT5 in cancer cells, as well as in the tumor microenvironment. Successful completion of this goal is likely to shed light on the unique dependencies of cancers on metabolic alterations, knowledge that can help the development of novel therapeutics for treating cancer. Based on the discovery of the novel enzymatic activity of SIRT5, we have developed small molecule inhibitors of SIRT5 that are very selective and do not inhibit other sirtuins. Some of the inhibitors have shown promising anticancer activity in cell culture and mouse models. Another goal of this proposal is to develop additional SIRT5 inhibitors with improved in vivo efficacies against cancer in mouse models. We are very excited about the robust translational potential of the project, which is based on strong fundamental understanding of the enzymatic activity and biochemistry of SIRT5, coupled with rigorous biological analyses in cultured cells and mice.