Targeting ferroptosis in cancer therapy

癌症治疗中的靶向铁死亡

• 批准号: 10581748
• 负责人: Boyi Gan
• 金额: $ 49.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581748
• 关键词: 5' -AMP-activated protein kinase; Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Anabolism; Antineoplastic Agents; Apoptosis; CRISPR screen; Cell Death; Cell Death Induction; Coenzyme A; Communities; Complex; Data; Development; Goals; Homeostasis; Iron; KRAS2 gene; Link; Lipid Peroxidation; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malonyl Coenzyme A; Mediating; Modality; Morphology; Outcome; Pathway interactions; Phosphorylation; Polyunsaturated Fatty Acids; Production; Publications; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Stress; TP53 gene; Testing; Therapeutic; Translating; Tumor Biology; Tumor Promotion; Tumor Suppression; cancer cell; cancer therapy; fatty acid biosynthesis; in vivo; innovation; interest; mouse model; mutant; novel; novel therapeutic intervention; pre-clinical; protein kinase inhibitor; sensor; targeted agent; therapeutic target; therapeutically effective; tumor

Project Summary Studying regulated cell death is critical for our understanding of tumor suppression and development of novel effective cancer therapy. Ferroptosis, an iron-dependent form of regulated cell death that is induced by excessive lipid peroxidation, is morphologically and mechanistically distinct from other forms of regulated cell death such as apoptosis. However, in contrast to our deep understanding of apoptosis, how ferroptosis is regulated and coordinates with other cellular signaling in tumor suppression remains much less well understood. There also exists a significant need to translate our understanding of ferroptosis mechanisms into effective cancer therapies. Our long-term goal is to understand the mechanism(s) of action of anti-neoplastic agents and/or combinations of agents that target ferroptosis in cancer therapy. The objective of this application is to determine the role and mechanisms of AMP-activated protein kinase (AMPK), a critical sensor of cellular energy status, in regulating ferroptosis and the relevance of these regulatory functions to tumor suppression and treatment. Energy stress depletes ATP and induces cell death. Surprisingly, our recent study revealed that energy stress can potently suppress ferroptotic cell death through activating AMPK. Cancer cells with high basal AMPK activation are resistant to ferroptosis, and AMPK inactivation sensitizes such cancer cells to ferroptosis. Our recent publication and new preliminary data support the central hypothesis that AMPK inhibits ferroptosis through AMPK-mediated phosphorylation of acetyl-CoA carboxylase (ACC) and biosynthesis of polyunsaturated fatty acid (PUFA) as well as other unidentified downstream effectors. AMPK can have either tumor-suppressive or -promoting functions, depending on the context. We further hypothesize that AMPK’s tumor-promoting function is at least partly mediated by its inhibition of ferroptosis, and combining AMPK inhibitors and ferroptosis inducers (FINs) is a novel therapeutic strategy for treating AMPK-dependent cancers. To test our hypotheses, we will pursue the following specific aims: Specific Aim 1: To study the mechanisms by which AMPK inhibits ferroptosis in cancer cells. Specific Aim 2: To determine the relevance of ferroptosis to AMPK-mediated tumor development and treatment. It is expected that our proposed studies will clarify how AMPK regulates PUFA biosynthesis, identify novel regulatory mechanisms of ferroptosis pathways, and reveal a previously unrecognized function of ferroptosis suppression in AMPK-mediated tumor promotion in cancer. Our proposal is highly innovative because it focuses on a previously unexplored pathway linking AMPK regulation of ferroptosis to tumor development. Our proposed studies will have significant impact on both our basic understanding of ferroptosis and our ability to target AMPK or ferroptosis in cancer treatment.

项目摘要 研究调节的细胞死亡对于我们对肿瘤抑制和发展的理解至关重要 新型有效的癌症治疗。铁毒性，一种由铁依赖性的调节细胞死亡形式，由 过度脂质过氧化在形态和机械上与其他形式的受调节细胞不同 死亡，例如凋亡。但是，与我们对细胞凋亡的深刻理解相反，铁凋亡是如何 在抑制肿瘤中，与其他细胞信号传导的调节和坐标的理解程度不高得多。 也有很大的需求将我们对铁毒机制的理解转化为有效 癌症疗法。我们的长期目标是了解抗塑性剂的作用机制 和/或靶向癌症治疗中铁凋亡的药物的组合。该应用的目的是 确定AMP激活蛋白激酶（AMPK）的作用和机制，AMPK）是细胞能的临界传感器 状态，控制铁铁作用以及这些调节功能与肿瘤抑制和 治疗。能量应力耗尽ATP并诱导细胞死亡。令人惊讶的是，我们最近的研究表明 能量应力可能会通过激活AMPK抑制铁毒细胞死亡。癌细胞高基础 AMPK激活对铁凋亡具有抗性，AMPK失活感知了此类癌细胞对铁凋亡的感觉。 我们最近的出版物和新的初步数据支持AMPK抑制铁铁病的中心假设 通过AMPK介导的乙酰辅酶A羧化酶（ACC）的磷酸化和多不饱和的生物合成 脂肪酸（PUFA）以及其他未识别的下游效应。 AMPK可以有肿瘤抑制 或 - 取决于上下文的功能。我们进一步假设AMPK的肿瘤促进 功能至少部分是由于其抑制螺栓毒性以及结合AMPK抑制剂和铁铁作用而介导的 诱导剂（FIN）是一种用于治疗AMPK依赖性癌症的新型治疗策略。为了检验我们的假设， 我们将追求以下特定目标：具体目的1：研究AMPK抑制的机制 癌细胞中的铁凋亡。特定目的2：确定铁凋亡与AMPK介导的肿瘤的相关性 开发和治疗。预计我们的拟议研究将阐明AMPK如何调节PUFA 生物合成，识别螺旋病途径的新型调节机制，并揭示了先前的 在AMPK介导的癌症促进AMPK介导的肿瘤抑制功能的功能。我们的建议是 高度创新性，因为它专注于以前出乎意料的途径，该途径连接了AMPK的螺旋病调节 进行肿瘤发育。我们提出的研究将对我们对的基本理解产生重大影响 在癌症治疗中靶向AMPK或铁凋亡的能力。