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 研究调节性细胞死亡对于我们理解肿瘤抑制和肿瘤的发展至关重要。 新的有效的癌症疗法。铁凋亡，一种铁依赖性的调节性细胞死亡形式， 过度的脂质过氧化，在形态上和机制上不同于其他形式的调节细胞 死亡，如凋亡。然而，与我们对细胞凋亡的深刻理解相反， 在肿瘤抑制中与其他细胞信号传导的调节和协调仍然没有得到很好的理解。 还存在将我们对铁凋亡机制的理解转化为有效的治疗的显著需要。 癌症治疗我们的长期目标是了解抗肿瘤药物的作用机制 和/或在癌症治疗中靶向铁凋亡的药剂的组合。本申请的目的是 确定AMP激活蛋白激酶（AMPK）的作用和机制，AMPK是细胞能量的关键传感器 状态，在调节铁凋亡和这些调节功能的相关性，肿瘤抑制和 治疗能量应激消耗ATP并诱导细胞死亡。令人惊讶的是，我们最近的研究表明， 能量应激可通过激活AMPK而有效抑制铁凋亡细胞的死亡。高基底细胞癌细胞 AMPK激活对铁凋亡具有抗性，而AMPK失活使此类癌细胞对铁凋亡敏感。 我们最近的出版物和新的初步数据支持AMPK抑制铁凋亡的中心假设 通过AMPK介导的乙酰辅酶A羧化酶（ACC）磷酸化和多不饱和脂肪酸的生物合成， 脂肪酸（PUFA）以及其他未鉴定的下游效应物。AMPK可以具有肿瘤抑制作用 或促进功能，这取决于上下文。我们进一步假设AMPK的促肿瘤作用 功能至少部分通过其对铁凋亡的抑制来介导，并且组合AMPK抑制剂和铁凋亡 诱导剂（FINs）是治疗AMPK依赖性癌症的一种新型治疗策略。为了验证我们的假设， 我们将追求以下具体目标：具体目标1：研究AMPK抑制 癌细胞中的铁凋亡具体目标2：确定铁凋亡与AMPK介导的肿瘤的相关性 发展和治疗。我们的研究将有助于阐明AMPK如何调节PUFA 生物合成，确定新的铁凋亡途径的调节机制，并揭示了以前的 铁凋亡抑制在癌症中AMPK介导的肿瘤促进中的未被认识的功能。我们的建议是 高度创新，因为它专注于以前未探索的连接AMPK调节铁凋亡的途径 肿瘤的发展。我们提出的研究将对我们的基本认识产生重大影响， 铁凋亡和我们在癌症治疗中靶向AMPK或铁凋亡的能力。