The Role of p53-inducible Sesn1 and Sesn2 genes in lung carcinogenesis

p53诱导的Sesn1和Sesn2基因在肺癌发生中的作用

• 批准号: 8789160
• 负责人: Andrei Vladimirovich Budanov
• 金额: $ 31.64万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789160
• 关键词: Address; Adenocarcinoma; Affect; Alpha 1 Casein Kinase 1; Autophagocytosis; Cancer Etiology; Cancer Model; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell Proliferation Regulation; Cell Survival; Cells; Cessation of life; DNA Damage; Depressed mood; Development; Diagnosis; Diagnostic; Disease; Epithelial Cell Proliferation; Gene Family; Genes; Genetic; Goals; Health; Human; K-ras mouse model; KRAS2 gene; Knockout Mice; Knowledge; Link; Lung; Malignant neoplasm of lung; Mediating; Mesenchymal; Metabolism; Mission; Modeling; Mus; Mutagenesis; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Outcome; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Property; Protein p53; Proto-Oncogenes; Public Health; Radiation therapy; Reactive Oxygen Species; Regulation; Research; Role; STK11 gene; Signal Pathway; Staging; Stress; Structure of parenchyma of lung; Suppressor Genes; Survival Rate; TP53 gene; Transcriptional Regulation; Tumor Angiogenesis; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft procedure; adenoma; angiogenesis; anticancer treatment; base; cancer cell; cancer initiation; cancer therapy; carcinogenesis; cell growth; design; human FRAP1 protein; improved; irradiation; lung carcinogenesis; mTOR Signaling Pathway; mTOR inhibition; mitochondrial dysfunction; mortality; mouse model; mutant; novel; novel strategies; overexpression; oxidative damage; response; trait; tumor; tumor growth

DESCRIPTION (provided by applicant): Around a million people are diagnosed with non-small cell lung cancer (NSCLC) worldwide each year and 85% of them will die during next 5 years. In spite of considerable efforts to improve the diagnostics and efficiency of treatment, the changes in mortality rate for the last couple decades is less than 2%. New effective approaches for anti-cancer therapy are hindered by the lack of knowledge of the mechanisms of lung carcinogenesis and a predictive strategy for efficient treatment. Among the genes dysregulated in NSCLC mutations in p53 and LKB1 are major traits, and their critical effect on lung carcinogenesis is supported by many mouse models. P53 suppresses carcinogenesis through transcriptional regulation of a number of genes, although the critical targets involved in tumor suppression are unknown. The LKB1 kinase phosphorylates and activates AMPK leading to inhibition of mTOR kinase, critical regulator of cell growth, proliferation and metabolism, which i activated in many lung cancers. Strikingly, similar to LKB1 p53 inhibits mTOR through activation of AMPK, although the inter-relation between p53- and LKB1-regulated signaling pathways is not well characterized. Recently we described a novel Sestrin (Sesn) gene family of stress-responsive genes in which expression is regulated in a p53-dependent manner. Sesns inhibit mTOR through AMPK regulation causing inhibition of cell growth and proliferation, activation of autophagy and protection against oxidative damage. Sesn1 and Sesn2 are downregulated in most human lung cancers and this leads to dysregulation of tumor growth and angiogenesis, so the Sesns are potential tumor suppressors and effectors of p53. The objective of the proposed work is to establish the importance of Sesn1 and Sesn2 in suppression of lung carcinogenesis and the outcome of anticancer treatment. To accomplish that we set up the following specific aims: Aim 1: To determine tumor suppressor properties of Sesn1 and Sesn2. We will apply of mouse model of K-ras-induced lung carcinogenesis and study whether inactivation or overexpression of Sesns modulate lung carcinogenesis. We will address the potential mechanisms, which involve regulation of cell proliferation and cell death, oxidative stress, autophagy and metabolism. Aim 2: To study the impact of the AMPK-mTOR pathway in regulation of carcinogenesis by Sesn1/2. We will analyze the role of Sesn1/2 in regulation of the AMPK-mTOR pathway in lung tissue and cancers and study whether the modulation of this pathway affects tumor-suppression function of Sesns. Aim 3: To understand the role of Sesn1/2 in anticancer treatment. We will treat Sesn1/2-deficient and proficient tumors and cancer cells with irradiation and DNA-damaging drugs and determine the impact of Sesn1/2 in tumor growth, cell viability and proliferation. The accomplishment of these goals let us to understand the mechanisms of tumor suppression in lung and design the more advanced approaches to diagnose and treat lung cancers decreasing the enormous death toll.

描述（由申请人提供）：每年在全球范围内被诊断出大约一百万人患有非小细胞肺癌（NSCLC），其中85％将在接下来的5年中死亡。尽管为提高治疗的诊断和效率做出了巨大努力，但过去几十年的死亡率变化却小于2％。缺乏对肺癌发生机制的知识和有效治疗的预测策略，阻碍了抗癌治疗的新有效方法。 在p53和LKB1中NSCLC突变失调的基因中，有主要特征，其对肺癌发生的关键作用得到了许多小鼠模型的支持。 p53通过许多基因的转录调节抑制了癌变，尽管涉及肿瘤抑制的关键靶标尚不清楚。 LKB1激酶磷酸化并激活AMPK，从而抑制MTOR激酶，这是细胞生长，增殖和代谢的关键调节剂，我在许多肺癌中都激活了这一点。令人惊讶的是，尽管p53-和LKB1调节的信号通路之间的相互关联尚未很好地表征，但类似于LKB1 p53通过激活AMPK抑制MTOR。 最近，我们描述了一种新型的Sestrin（SESN）基因胁迫响应基因的基因，其中表达以p53依赖性方式调节。 SESN通过AMPK调节抑制MTOR，从而抑制细胞生长和增殖，激活自噬和防止氧化损伤。在大多数人类肺癌中，SESN1和SESN2被下调，这导致肿瘤生长和血管生成失调，因此SESN是p53的潜在肿瘤抑制因子和效应子。拟议工作的目的是确定SESN1和SESN2在抑制肺癌发生和抗癌治疗结果中的重要性。为此，我们设置了以下特定目标：目标1：确定sesn1和sesn2的肿瘤抑制特性。我们将应用K-RAS诱导的肺癌发生的小鼠模型，并研究SESN的失活或过表达调节肺癌。我们将解决潜在的机制，其中涉及细胞增殖和细胞死亡，氧化应激，自噬和代谢的调节。 目标2：研究AMPK-MTOR途径对SESN1/2调节致癌作用的影响。 我们将分析SESN1/2在肺组织和癌症中AMPK-MTOR途径调节中的作用，并研究该途径的调节是否影响SESN的肿瘤支持功能。 目标3：了解SESN1/2在抗癌治疗中的作用。 我们将使用辐照和减轻DNA的药物治疗SESN1/2缺陷且熟练的肿瘤和癌细胞，并确定SESN1/2对肿瘤生长，细胞活力和增殖的影响。 这些目标的实现使我们能够理解肺部肿瘤抑制的机制，并设计了更先进的诊断和治疗肺癌的方法，从而减少了巨大的死亡人数。