Regulation of Mitochondrial Metabolism by Tyr-phosphorylated ATP Synthase Alpha-Subunit and its Therapeutic Implications in Prostate Cancer

酪氨酸磷酸化 ATP 合酶 α 亚基对线粒体代谢的调节及其在前列腺癌中的治疗意义

• 批准号: 10657090
• 负责人: Nupam P Mahajan
• 金额: $ 47.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657090
• 关键词: ACK1 Gene; ATP Synthesis Pathway; ATP phosphohydrolase; Acute; Binding; Categories; Cause of Death; Data; Dependence; Disease remission; Enzyme Stability; Exclusion; In Situ; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Mitochondria; Molecular; Nucleotides; Oncogenic; Oxidative Phosphorylation; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Process; Proliferating; Property; Prostate; Protein Tyrosine Kinase; Proteins; Regulation; Resistance; Resistance development; Role; Signal Transduction; Structure; Surface; Therapeutic; Tyrosine Kinase Inhibitor; abiraterone; addiction; antagonist; cancer cell; cancer therapy; castration resistant prostate cancer; enzalutamide; flexibility; in vivo; inhibitor; men; metabolic phenotype; mitochondrial metabolism; mouse model; patient derived xenograft model; prevent; prostate cancer model; prostate cancer progression; response; tumor; tumor growth

Project Abstract Cancer cell mitochondria switch their metabolic phenotypes to meet the challenges of high-energy demand and macromolecular synthesis. Acute dependence of tumors on oncogenic tyrosine kinase signaling support their rapid proliferation, however, direct relevance of the kinase activity for mitochondria to support these high-energy processes remains obscure. Serendipitously, we uncovered that a non-receptor tyrosine kinase, ACK1, phosphorylates ATP synthase F1 α-subunit (ATP5F1a) at Tyr243 and Tyr246 (Tyr200 & 203 in mature protein, respectively) that increased ATP synthase activity specifically in the cancer cells. Mechanistically, ATP5F1a- phosphorylation not only excluded its binding to its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), but also created a supporting structure that extended from the bound non-catalytic nucleotide to the surface, reducing the flexibility and thereby increasing the stability of the enzyme. A new class of ACK1 inhibitor, (R)-9b reversed this process, inducing mitophagy and mitigating tumor growth. Consistently, a marked increase in ATP5F1a-phosphorylations was observed as normal prostate progressed to the malignant stage. Overall, these data provide the molecular evidence for cancer cell `mitochondrial addiction’ to Tyr-kinase indulgence, and reveals (R)-9b as a ‘mitocan’ that compromises the unique metabolic needs of cancer cells. Castration resistant prostate cancer (CRPC) remains an incurable malignancy with limited treatment options and is a significant cause of deaths in men worldwide (15). Limited efficacy and rapid development of resistance for Enzalutamide and Abiraterone, AR antagonist treatment have established a new paradigm-to achieve realistic remission, other cancer specific pathways, including metabolic must be compromised. This proposal is directed towards detailed characterization of mitochondrial metabolism modulatory properties of ACK1/ATP5F1a signaling and examine ability of (R)-9b to overcome Enzalutamide and abiraterone-resistant CRPCs. The specific aims are as follows: Specific Aim 1. Examine the mechanism by which ATP5F1a-phosphorylation regulates its activity in prostate cancer Specific Aim 2. Explore the role of ACK1/ATP5F1a signaling in prostate cancer models Specific Aim 3. Detail in vivo characterization of ACK1/ATP5F1a signaling in enzalutamide and abiraterone- resistance in mouse models of prostate cancer and patient derived xenografts (PDXs)

项目摘要 癌细胞线粒体改变其代谢表型以应对高能量需求的挑战 大分子合成。肿瘤对致癌酪氨酸激酶信号的急性依赖性支持它们。 然而，快速增殖，线粒体激酶活性直接相关，以支持这些高能 偶然地，我们发现了一种非受体酪氨酸激酶 ACK1， 在 Tyr243 和 Tyr246（成熟蛋白中的 Tyr200 和 203）处磷酸化 ATP 合酶 F1 α 亚基 (ATP5F1a)， 分别），从机制上讲，ATP5F1a-特别增加了癌细胞中的ATP合酶活性。 磷酸化不仅排除了其与其生理抑制剂 ATP 酶抑制因子 1 (IF1) 的结合，而且 还创建了一个从结合的非催化核苷酸延伸到表面的支撑结构， 降低灵活性，从而提高酶的稳定性 一类新型 ACK1 抑​​制剂 (R)-9b。 逆转了这一过程，诱导线粒体自噬并减轻肿瘤生长。 当正常前列腺进展到恶性阶段时观察到 ATP5F1a 磷酸化。 数据提供了癌细胞对酪氨酸激酶“线粒体成瘾”的分子证据，以及 揭示 (R)-9b 是一种“线粒体蛋白聚糖”，会损害癌细胞独特的代谢需求。 去势抵抗性前列腺癌（CRPC）仍然是一种无法治愈的恶性肿瘤，治疗选择有限，并且 是全世界男性死亡的一个重要原因 (15)。 恩杂鲁胺和阿比特龙，AR拮抗剂治疗建立了新范式——实现现实 缓解期间，其他癌症特定途径，包括代谢途径必须受到损害。 ACK1/ATP5F1a 线粒体代谢调节特性的详细表征 (R)-9b 的信号传导和检查能力克服恩杂鲁胺和阿比特龙耐药的 CRPC。 具体目标如下： 具体目标 1. 检查 ATP5F1a 磷酸化在前列腺中调节其活性的机制 癌症 具体目标2.探讨ACK1/ATP5F1a信号在前列腺癌模型中的作用 具体目标 3. 恩杂鲁胺和阿比特龙中 ACK1/ATP5F1a 信号传导的详细体内表征 前列腺癌小鼠模型和患者来源的异种移植物 (PDX) 中的耐药性