(PQA1) Molecular Mechanism of Metformin in Cancer

描述（由申请人提供）：二甲双胍是一种广泛使用的抗糖尿病药物，由于其有趣的抗肿瘤作用，最近引起了广泛关注。然而，尽管越来越多的证据支持二甲双胍在癌症预防和治疗中的有效性，但其潜在机制仍然知之甚少。由热休克因子1（HSF 1）介导的蛋白毒性应激反应是一种进化上保守的适应性机制，其在面对来自外部和内部的各种各样的应激源时增强细胞和生物体的存活。与这种公认的有益作用形成鲜明对比的是，新兴的研究已经开始揭示这种应激反应在促进肿瘤发生中的惊人作用。 根据我们的初步结果，我们假设二甲双胍部分通过抑制HSF 1介导的蛋白毒性应激反应并随后破坏癌症蛋白稳态来发挥其抗癌作用。本提案的目的是确定二甲双胍抑制HSF 1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。将追求两个具体目标：目标1）确定二甲双胍是否通过生物化学和遗传学方法激活关键代谢传感器AMPK信号传导来抑制HSF 1，将研究二甲双胍调节HSF 1的分子机制;目标2）确定二甲双胍是否使HSF 1失活，从而破坏蛋白质稳态，从而发挥其抗癌作用。这将在遗传性黑素瘤异种移植模型中进行测试。该项目的成功完成将阐明二甲双胍保护癌症发病率和死亡率的新分子作用机制，这对正在进行的二甲双胍临床试验特别有指导意义。更重要的是，鉴于HSF 1在广泛的人类癌症中的新作用，该项目的成功将验证靶向HSF 1介导的应激反应作为一种有前途的抗癌策略。

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.