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: 9198533
• 负责人: Steven R. Grossman
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198533
• 关键词: Address; Adenocarcinoma; Affect; 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; FRAP1 gene; Gene Family; Genes; Genetic; Goals; Human; Impairment; 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; Reactive Oxygen Species; Regulation; Research; Role; STK11 gene; Signal Pathway; Stress; Structure of parenchyma of lung; Suppressor Genes; Survival Rate; TP53 gene; Transcriptional Regulation; Tumor Angiogenesis; Tumor Suppression; Tumor Suppressor Proteins; United States National Institutes of Health; Work; Xenograft procedure; adenoma; angiogenesis; anticancer treatment; base; cancer cell; cancer initiation; cancer therapy; carcinogenesis; cell growth; chemoradiation; design; improved; irradiation; lung carcinogenesis; mTOR Signaling Pathway; mTOR inhibition; mitochondrial dysfunction; mortality; mouse model; mutant; neoplastic cell; novel; novel strategies; overexpression; oxidative damage; public health relevance; 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（申请人提供）：全世界每年约有一百万人被诊断患有非小细胞肺癌（NSCLC），其中 85% 将在未来 5 年内死亡。尽管在改善诊断和治疗效率方面付出了巨大努力，但过去几十年死亡率的变化仍不到 2%。由于缺乏对肺癌发生机制的了解和有效治疗的预测策略，新的有效抗癌治疗方法受到阻碍。 在 NSCLC 基因失调中，p53 和 LKB1 突变是主要特征，许多小鼠模型都支持它们对肺癌发生的关键作用。尽管参与肿瘤抑制的关键靶标尚不清楚，但 P53 通过许多基因的转录调节来抑制癌变。 LKB1 激酶磷酸化并激活 AMPK，从而抑制 mTOR 激酶，mTOR 激酶是细胞生长、增殖和代谢的关键调节因子，在许多肺癌中被激活。引人注目的是，与 LKB1 类似，p53 通过激活 AMPK 抑制 mTOR，尽管 p53 和 LKB1 调节的信号通路之间的相互关系尚未得到很好的表征。 最近，我们描述了一种新的应激反应基因 Sestrin (Sesn) 基因家族，其中表达以 p53 依赖性方式受到调节。 Sesns 通过 AMPK 调节抑制 mTOR，从而抑制细胞生长和增殖、激活自噬并防止氧化损伤。 Sesn1 和 Sesn2 在大多数人类肺癌中表达下调，这会导致肿瘤生长和血管生成失调，因此 Sesn 是潜在的肿瘤抑制因子和 p53 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。为了实现这一目标，我们设定了以下具体目标： 目标 1：确定 Sesn1 和 Sesn2 的肿瘤抑制特性。我们将应用K-ras诱导肺癌的小鼠模型，研究Sesns的失活或过度表达是否调节肺癌的发生。我们将探讨潜在的机制，包括细胞增殖和细胞死亡的调节、氧化应激、自噬和代谢。 目标 2：研究 AMPK-mTOR 通路在 Sesn1/2 调控癌发生中的影响。 我们将分析Sesn1/2在肺组织和癌症中AMPK-mTOR通路的调节作用，并研究该通路的调节是否影响Sesn的抑癌功能。 目标 3：了解 Sesn1/2 在抗癌治疗中的作用。 我们将用辐射和 DNA 损伤药物治疗 Sesn1/2 缺陷和丰富的肿瘤和癌细胞，并确定 Sesn1/2 对肿瘤生长、细胞活力和增殖的影响。 这些目标的实现让我们了解肺部肿瘤抑制机制，并设计更先进的方法来诊断和治疗肺癌，从而减少巨大的死亡人数。

项目成果

Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.

• DOI: 10.1126/scitranslmed.aak9969
• 发表时间: 2017-06-28
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Oricchio E;Katanayeva N;Donaldson MC;Sungalee S;Pasion JP;Béguelin W;Battistello E;Sanghvi VR;Jiang M;Jiang Y;Teater M;Parmigiani A;Budanov AV;Chan FC;Shah SP;Kridel R;Melnick AM;Ciriello G;Wendel HG
• 通讯作者: Wendel HG

p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis.

• DOI: 10.18632/oncotarget.27367
• 发表时间: 2019-12-10
• 期刊: Oncotarget
• 作者: Ding, Boxiao;Haidurov, Alexander;Budanov, Andrei V
• 通讯作者: Budanov, Andrei V

Harnessing the vulnerabilities of p53 mutants in lung cancer - Focusing on the proteasome: a new trick for an old foe?

• DOI: 10.1080/15384047.2019.1702403
• 发表时间: 2020-04-02
• 期刊: Cancer biology & therapy
• 影响因子: 3.6
• 作者: Oduah EI;Grossman SR
• 通讯作者: Grossman SR

The role of tumor suppressor p53 in the antioxidant defense and metabolism.

• DOI: 10.1007/978-94-017-9211-0_18
• 发表时间: 2014
• 期刊: Sub-cellular biochemistry
• 作者: Budanov, Andrei V