(PQA1) Molecular Mechanism of Metformin in Cancer

(PQA1) 二甲双胍抗癌的分子机制

• 批准号: 8685391
• 负责人: Chengkai Dai
• 金额: $ 19.03万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685391
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Address; Adverse effects; Affect; Aminoimidazole Carboxamide; Animals; Antidiabetic Drugs; Antineoplastic Agents; Attention; Biochemical Genetics; Biological; Biological Markers; Cancer Biology; Cells; Clinical; Clinical Trials; DNA Binding; Data; Development; Diabetes Mellitus; Effectiveness; Environment; FDA approved; Face; Genetic; Goals; Growth; Heat Stress Disorders; Heat shock proteins; Homeostasis; Human; Incidence; Lead; Light; Malignant - descriptor; Malignant Neoplasms; Mediating; Melanoma Cell; Metabolic; Metformin; Molecular; Molecular Mechanisms of Action; Nerve Degeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Polyubiquitination; Proteins; Proteome; Regulation; Ribonucleotides; Role; STK11 gene; Signal Transduction; Stress; Testing; Treatment Efficacy; Tumor Suppressor Proteins; Xenograft Model; addiction; base; biological adaptation to stress; cancer cell; cancer prevention; cancer risk; cancer therapy; clinically relevant; environmental stressor; heat-shock factor 1; in vivo; malignant phenotype; melanoma; mortality; neoplastic; novel; prevent; protein degradation; protein expression; public health relevance; sensor; stressor; success; tumorigenesis

DESCRIPTION (provided by applicant): Metformin, a widely prescribed anti-diabetic drug, has recently drawn much attention due to its intriguing anti- neoplastic effects. However, despite the increasing body of evidence supporting metformin's effectiveness in cancer prevention and therapy, the underlying mechanisms remain poorly understood. The proteotoxic stress response, mediated by Heat shock factor 1 (HSF1), is an evolutionarily conserved adaptive mechanism that enhances cellular and organismal survival in face of a wide variety of stressors from without and within. In sharp contrast to this well-recognized beneficial effect, emerging studies have begun to reveal a surprising role of this stress response in facilitating oncogenesis. Based on our preliminary results, we hypothesize that metformin exerts its anti-cancer effects in part through suppressing the HSF1-mediated proteotoxic stress response and subsequently disrupting cancer proteostasis. The objectives of this proposal are to define the molecular mechanisms by which metformin suppresses HSF1 and to determine whether this suppression contributes to metformin's anti-cancer effects. Two specific aims will be pursued: Aim 1) Determine whether metformin suppresses HSF1 through activation of the key metabolic sensor AMPK signaling by biochemical and genetic approaches, the molecular mechanisms by which metformin regulates HSF1 will be interrogated; Aim 2) Determine whether metformin inactivates HSF1 and consequently disrupts proteostasis, thereby exerting its anti-cancer effects. This will be tested in a genetic melanoma xenograft model. Successful completion of this project will elucidate a new molecular mechanism of action by which metformin protects against cancer incidence and mortality, which would be particularly instructive to the numerous ongoing clinical trials of metformin. More importantly, in light of the emerging role of HSF1 in a broad spectrum of human cancers, success of this project will authenticate targeting the HSF1-mediated stress response as a promising anti-cancer strategy in general.

描述（由申请人提供）：二甲双胍是一种广泛规定的抗糖尿病药物，由于其引人入胜的抗肿瘤作用，最近引起了很多关注。然而，尽管有越来越多的证据支持二甲双胍在预防癌症和治疗方面的有效性，但基本机制仍然知之甚少。由热休克因子1（HSF1）介导的蛋白毒性应激反应是一种进化保守的自适应机制，它在面对各种胁迫源的情况下从没有和内部的多种应激源来增强细胞和生物的生存。与这种公认的有益效果形成鲜明对比，新兴的研究开始揭示了这种压力反应在促进肿瘤发生中的令人惊讶的作用。 基于我们的初步结果，我们假设二甲双胍通过抑制HSF1介导的蛋白毒性应激反应并随后破坏癌症蛋白质症来部分抑制其抗癌作用。该提案的目标是定义二甲双胍抑制HSF1的分子机制，并确定这种抑制是否有助于二甲双胍的抗癌作用。将实现两个具体的目标：目标1）确定二甲双胍是否通过生化和遗传方法激活关键代谢传感器AMPK信号传导是否抑制HSF1，该分子机制会调节HSF1的分子机制；目的2）确定二甲双胍是否使HSF1失活并因此破坏蛋白质量，从而发挥其抗癌作用。这将在遗传黑色素瘤异种移植模型中进行测试。该项目的成功完成将阐明一种新的分子作用机制，二甲双胍可以预防癌症的发病率和死亡率，这对于众多二甲双胍的临床试验尤其具有启发性。更重要的是，鉴于HSF1在人类广泛的癌症中的新兴作用，该项目的成功将对针对HSF1介导的压力反应的靶向作为一般有希望的反癌策略。