Succinylation and Malonylation as Novel Protein Modifications in Cancer

琥珀酰化和丙二酰化作为癌症中的新型蛋白质修饰

• 批准号: 8507473
• 负责人: RICHARD A. CERIONE
• 金额: $ 56.73万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507473
• 关键词: ADP ribosylation; Active Sites; Affect; Alleles; Animal Model; Attention; Basic Science; Binding; Biochemistry; Bioenergetics; Biological Assay; Breeding; Cancer Patient; Cell Culture System; Cell Culture Techniques; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular biology; Cessation of life; Data; Deacetylation; Development; Disease; Drug Targeting; Effectiveness; Embryo; Enzymatic Biochemistry; Enzymes; Epidermal Growth Factor Receptor; Event; Exhibits; Family member; Fibroblasts; Genetic; Genetic Models; Glutamate Dehydrogenase; Glutamine; Goals; Growth; Human; Intervention; Knockout Mice; Laboratories; Lung; Lung Adenocarcinoma; Lysine; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Metabolic Pathway; Metabolism; Mitochondrial Proteins; Modeling; Modification; Molecular; Mutation; Nature; Nicotinamide adenine dinucleotide; Oncogenes; Organic Chemistry; Peptides; Phenotype; Play; Post-Translational Protein Processing; Property; Protein Family; Proteins; Reagent; Regulation; Research; Resistance; Role; Series; Sirtuins; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Validation; Warburg Effect; addiction; base; cancer cell; cell transformation; cellular targeting; chemotherapy; clinical application; design; effective therapy; inhibitor/antagonist; interest; lung tumorigenesis; malignant breast neoplasm; malignant state; member; metaplastic cell transformation; mouse model; neoplastic; new therapeutic target; novel; novel strategies; novel therapeutics; programs; research and development; research study; small molecule; therapeutic target; treatment strategy; tumor metabolism; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The lack of effective treatments for many cancers and the occurence of resistance to available therapies make it critically important to identify new targets and strategies for intervention against a number of human malignancies. This multi-PI-directed study will set out to establish the importance of previously unrecognized, reversible protein posttranslational modifications (lysine succinylation and malonylation) in the development of the malignant state. The studies described in this application arise from two exciting new research developments. The first is based on our very recent discovery suggesting the existence of novel post-translational protein modifications on several metabolic enzymes in cells. These modifications appear to be regulated by the mitochondrial protein Sirt5, a member of the Sir2 family of proteins (for Silent information regulator 2). The second involves the renewed attention being directed toward understanding the roles played by cellular metabolism in cancer progression. This is especially the case for the enhanced glycolytic activity (the "Warburg effect") and markedly elevated glutamine metabolism (i.e. "glutamine addiction") exhibited by cancer cells. When combined with our preliminary findings suggesting that Sirt5 is required for the transformed phenotypes of a number of human cancer cells, these different pieces of evidence have led us to put forward the novel hypothesis that the desuccinylation and/or demalonylation of key enzymes in cancer metabolism are essential for satisfying the biosynthetic and bioenergetic requirements of malignant transformation. We will test this hypothesis in cell culture experiments (Aim 1) and mouse models (Aim 2), as well as delineate the molecular mechanisms underlying the requirement of demalonylation/desuccinylation for the malignant state of cancer cells (Aim 1). Moreover, we believe that targeting Sirt5 and blocking its ability to regulate these post-translational modifications in cancer cells will offer new approaches for intervention against this disease. We will identify novel small molecule inhibitors that specifically target Sirt5 (Aim 3) and demonstrate their effectiveness at blocking malignant transformation in cell culture (Aim 1) and in a mouse model of Kras-induced lung cancer (Aim 2), a malignancy for which the development of new therapeutic strategies is especially needed. While a subset of lung cancers can be treated successfully with EGF receptor inhibitors, the approximately 25-50% of lung adenocarcinomas harboring Kras mutations are resistant to these inhibitors as well as chemotherapy, and clinically effective drugs targeting Kras have remained elusive. Thus, we feel that developing strategies that target these novel Sirt5-regulated post- translational modifications as a means to help 're-set' the altered metabolism of cancer cells represents a transformative approach that could ultimately prove beneficial to lung cancer patients, as well as provide a general therapeutic benefit against a broad range of human malignancies, given the fundamental nature of metabolic alterations in cancer.

描述（由申请人提供）：许多癌症缺乏有效的治疗方法以及对现有疗法的耐药性的出现，使得确定针对多种人类恶性肿瘤进行干预的新靶点和策略变得至关重要。这项多 PI 导向的研究将着手确定以前未被识别的可逆蛋白质翻译后修饰（赖氨酸琥珀酰化和丙二酰化）在恶性状态发展中的重要性。本申请中描述的研究源于两项令人兴奋的新研究进展。第一个基于我们最近的发现，表明细胞中的几种代谢酶存在新型翻译后蛋白质修饰。这些修饰似乎受到线粒体蛋白 Sirt5 的调节，Sirt5 是 Sir2 蛋白家族的成员（沉默信息调节器 2）。第二个涉及重新关注理解细胞代谢在癌症进展中所发挥的作用。尤其是癌细胞表现出的糖酵解活性增强（“瓦伯格效应”）和谷氨酰胺代谢显着升高（即“谷氨酰胺成瘾”）。结合我们的初步研究结果表明，Sirt5是许多人类癌细胞转化表型所必需的，这些不同的证据使我们提出了新的假设，即癌症代谢中关键酶的脱琥珀酰化和/或脱丙酰化对于满足恶性转化的生物合成和生物能要求至关重要。我们将在细胞培养实验（目标 1）和小鼠模型（目标 2）中测试这一假设，并描述癌细胞恶性状态需要脱丙二酰化/去琥珀酰化的分子机制（目标 1）。此外，我们相信，针对 Sirt5 并阻断其调节癌细胞中这些翻译后修饰的能力将为干预这种疾病提供新的方法。我们将鉴定特异性靶向 Sirt5 的新型小分子抑制剂（目标 3），并证明其在细胞培养物（目标 1）和 Kras 诱导肺癌小鼠模型（目标 2）中阻止恶性转化的有效性，针对这种恶性肿瘤，特别需要开发新的治疗策略。虽然一部分肺癌可以用 EGF 受体抑制剂成功治疗，但大约 25-50% 的携带 Kras 突变的肺腺癌对这些抑制剂和化疗具有耐药性，临床上有效的针对 Kras 的药物仍然难以捉摸。因此，我们认为，开发针对这些新型 Sirt5 调节的翻译后修饰的策略，作为帮助“重置”癌细胞改变的代谢的手段，代表了一种变革性方法，最终可能证明对肺癌患者有益，并鉴于癌症代谢改变的基本性质，为广泛的人类恶性肿瘤提供普遍的治疗益处。