Targeting the dependency of cancer cells on the sirtuin SIRT5

靶向癌细胞对 Sirtuin SIRT5 的依赖性

基本信息

批准号：
10369635
负责人：
RICHARD A. CERIONE
金额：
$ 40.41万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369635
关键词：
Adherent Culture Affect Agar Anchorage-Independent Growth Antineoplastic Agents Biochemistry Biological Biological Assay Breast Breast Cancer Model Cancer Cell Growth Cancer Model Cell Culture Techniques Cell membrane Cell model Cell physiology Cells Charge Citric Acid Cycle Coupled Cultured Cells Data Deacetylation Dependence Development Elements Endothelium Enzymes Evaluation Family Foundations Future Genetic Glutaminase Glutamine Goals Growth Immune Impairment In Vitro Knockout Mice Knowledge Light Longevity Lysine Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Modification Molecular Mouse Mammary Tumor Virus Mus NADP Nature Neoplasm Metastasis Normal Cell Permeability Pharmaceutical Preparations Physiology Play Post-Translational Protein Processing Prodrugs Proliferating Property Proteins Proteomics RNA interference screen Reactive Oxygen Species Regulation Resistance development Role Serum Sirtuins Structure Testing Therapeutic Transcriptional Regulation Transgenic Mice Transplantation Tumor Burden Xenograft procedure anti-cancer anticancer activity base cancer cell cancer heterogeneity cell transformation clinical development deacylation efficacy testing improved in vitro Assay in vivo inhibitor interest malignant breast neoplasm member mouse model neoplastic cell novel novel anticancer drug novel therapeutics overexpression patient derived xenograft model prevent small molecule small molecule inhibitor therapeutic development therapeutic target therapy resistant translational potential treatment strategy tumor tumor microenvironment tumorigenesis

项目摘要

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.

由于癌症的异质性和对新抗癌药物的需求仍然很大对现有药物产生耐药性。这项合作提案由三位 PI（Richard Cerione、 Hening Lin 和 Robert Weiss）旨在将 SIRT5 抑制建立为治疗癌症的新策略。 SIRT5 是一个 Sirtuin 酶家族的成员，已知具有 NAD+ 依赖性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、代谢和代谢的调节。寿命。我们是第一个发现 SIRT5（一种脱乙酰活性非常弱的线粒体去乙酰化酶）的人，更喜欢水解带负电荷的酰基赖氨酸修饰，例如琥珀酰和丙二酰赖氨酸，蛋白质。我们和其他人已经将赖氨酸琥珀酰化确定为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兴奋的初步数据显示 SIRT5 缺失会损害小鼠的肿瘤发生和转移。在细胞水平上，我们发现灭活 SIRT5 可抑制癌细胞的锚定非依赖性生长，但在某些情况下几乎没有作用对传统单层培养物增殖的影响。我们假设 SIRT5 介导的调节新陈代谢是恶性转化和获得锚定等特性所必需的独立生长和侵袭性。拟议研究的目标之一是了解详细的 SIRT5 在癌细胞以及肿瘤微环境中的分子功能。顺利完成这一目标可能会揭示癌症对代谢改变、知识的独特依赖性这可以帮助开发治疗癌症的新疗法。根据小说的发现由于 SIRT5 的酶活性，我们开发了 SIRT5 的小分子抑制剂，具有非常高的选择性和不抑制其他去乙酰化酶。一些抑制剂在细胞培养中显示出有希望的抗癌活性，鼠标模型。该提案的另一个目标是开发额外的 SIRT5 抑制剂，以改善体内在小鼠模型中具有抗癌功效。我们对该技术强大的转化潜力感到非常兴奋该项目基于对酶活性和生物化学的深刻理解 SIRT5，加上对培养细胞和小鼠进行严格的生物学分析。