Sirt2 Directs Kras IR Cell Resistance and Tumorigenesis

Sirt2 指导 Kras IR 细胞耐药性和肿瘤发生

基本信息

批准号：
9262169
负责人：
Athanasios Vasilopoulos
金额：
$ 32.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-06 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262169
关键词：
Acetylation Address Adenocarcinoma Cell Affect Age Aging Alpha Cell Amino Acid Substitution Amino Acids Antibodies Antineoplastic Agents Biochemical Biological Models Caenorhabditis elegans Cancer Patient Carcinogenesis Mechanism Carcinoma in Situ Cells Deacetylation Development Elderly Environment Event Exhibits Exposure to Family Frequencies Future Genes Genetic Genomic Instability Genomics Grant Harvest Human Hyperplasia Impairment In Vitro Incidence Infection Investigation Ionizing radiation KRAS2 gene Knock-out Knockout Mice Knowledge Link Longevity Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Modeling Molecular Molecular Target Mus Mutate Mutation Organism Phenotype Play Post-Translational Protein Processing Prevention Process Property Proteins Refractory Research Research Proposals Resistance Role Saccharomyces cerevisiae Sampling Signal Transduction Sirtuins Site Smoking Subgroup Testing Therapeutic Time Tumor Suppressor Proteins age related aging gene anticancer research cancer cell cancer therapy carcinogenesis cell growth chemotherapy design experimental study in vitro Model in vivo in vivo Model innovation lung Carcinoma mouse model mutant neoplastic cell oncology permissiveness personalized cancer therapy proteomic signature public health relevance targeted treatment tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): One idea of personalized cancer therapy is to identify specific subgroups of cancer patients that will benefit from specific therapeutic strategies. Recently, the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research identified as the NCI's "Provocative Questions". This research proposal, while not specifically submitted as a NCI PQ grant, does address one such question "How does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In this regard, it is proposed that the cytoplasmic sirtuin, SIRT2 is a tumor suppressor protein and the deletion of these proteins in mice has resulted in the creation of several new murine models for the investigation of illness that have a strong genetic connection to aging. Human cancers, including lung adenocarcinomas increase as a function of increasing age, as well as the result of smoking. As such, it is proposed that cells lacking Sirt2, or exhibiting decreased SIRT2 deacetylation activity exhibit increased KRAS activity and this plays a role, at least in part, in the establishment of a lung adenocarcinoma-permissive phenotype. Since activated KRAS mutations are a hallmark in LACa this raises an intriguing question: is it possible that acetylation of KRAS can function as a rheostat to direct activity that is an early event in the initiation of lung adenocarcinomas? We propose that the answer is yes. In addition, identifying a post translational modification which regulates KRAS activity could have important therapeutic implications. First, there are no effective targeted therapies for Ras-driven cancers and, second, impaired activity of KRAS, as it happens when the protein is mutated, is involved in the chemotherapy (CT) and ionizing radiation (IR) tumor cell resistance. Given that KRAS-related cancers are generally refractory to standard therapies due to activated downstream signaling, the finding that acetylation may regulate its activity could reveal a promising therapeutic approach for these malignancies.

描述（由申请人提供）：个性化癌症治疗的一个想法是确定将从特定治疗策略中受益的特定癌症患者亚组。最近，NCI提出了一个新的研究重点，即设计严谨和创新的研究策略，以解决癌症研究中被确定为NCI“挑衅性问题”的具体问题和悖论。这项研究提案虽然没有专门作为 NCI PQ 拨款提交，但确实解决了这样一个问题：“生物体的寿命如何影响癌症发展的分子机制，我们是否可以利用我们对衰老的深入了解来加强癌症的预防或治疗？”在这方面，有人提出细胞质去乙酰化酶（SIRT2）是一种肿瘤抑制蛋白，在小鼠中删除这些蛋白已导致创建了几种新的小鼠模型，用于研究与癌症有密切遗传联系的疾病。人类的衰老。癌症（包括肺腺癌）随着年龄的增长以及吸烟而增加。因此，有人提出，缺乏 Sirt2 或表现出 SIRT2 去乙酰化活性降低的细胞会表现出 KRAS 活性增加，这至少起到了一定作用。在某种程度上，在肺腺癌允许表型的建立中，由于激活的 KRAS 突变是 LACa 的一个标志，这提出了一个有趣的问题：是否有可能乙酰化。 KRAS 可以作为变阻器来指导肺腺癌发生的早期事件的活动吗？我们建议答案是肯定的。此外，识别调节 KRAS 活性的翻译后修饰可能具有重要的治疗意义。首先，对于 Ras 驱动的癌症没有有效的靶向治疗，其次，当蛋白质突变时，KRAS 活性受损，从而参与化疗 (CT) 和电离辐射 (IR) 肿瘤细胞抵抗。鉴于 KRAS 相关癌症由于激活的下游信号传导而通常对标准疗法难以治疗，乙酰化可能调节其活性的发现可能为这些恶性肿瘤提供一种有前途的治疗方法。