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：
8719606
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/8719606
关键词：
Acetylation Address Adenocarcinoma Cell Affect Age Aging Amino Acid Substitution Amino Acids Antibodies Antineoplastic Agents Biochemical Biological Models Caenorhabditis elegans Proteins Cancer Patient Carcinogenesis Mechanism Carcinoma in Situ Cells Deacetylation Development Elderly Environment Event Exhibits Exposure to Family Figs - dietary Frequencies Future Genes Genetic Genomic Instability Genomics Grant Harvest Homologous Gene Human Hyperplasia 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 Proteomics Refractory Research Research Proposals Resistance Role Saccharomyces cerevisiae Sampling Second Primary Cancers 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 in vitro Model in vivo in vivo Model innovation lung Carcinoma mutant neoplastic cell oncology public health relevance research study 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种想法是确定将受益于特定治疗策略的癌症患者的特定亚组。最近，NCI提出了一种新的研究重点，以设计严格而创新的研究策略，以解决被确定为NCI的“挑衅性问题”的癌症研究中的特定问题和悖论。 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腺癌 - 抗药性表型。我们建议答案是肯定的。此外，确定调节KRAS活动的翻译后修饰可能具有重要的治疗意义。首先，没有针对RAS驱动的癌症的有效靶向疗法，其次，KRAS的活性受损，因为它在蛋白质突变时发生，参与化学疗法（CT）和电离辐射（IR）肿瘤细胞耐药性。鉴于与KRAS相关的癌症通常由于激活的下游信号传导而对标准疗法难治性，因此乙酰化可能调节其活性的发现可能揭示了这些恶性肿瘤的有希望的治疗方法。