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
基本信息
- 批准号:10657090
- 负责人:
- 金额:$ 47.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ACK1 GeneATP Synthesis PathwayATP phosphohydrolaseAcuteBindingCategoriesCause of DeathDataDependenceDisease remissionEnzyme StabilityExclusionIn SituMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of prostateMetabolicMitochondriaMolecularNucleotidesOncogenicOxidative PhosphorylationPathway interactionsPhosphorylationPhosphotransferasesPhysiologicalProcessProliferatingPropertyProstateProtein Tyrosine KinaseProteinsRegulationResistanceResistance developmentRoleSignal TransductionStructureSurfaceTherapeuticTyrosine Kinase Inhibitorabirateroneaddictionantagonistcancer cellcancer therapycastration resistant prostate cancerenzalutamideflexibilityin vivoinhibitormenmetabolic phenotypemitochondrial metabolismmouse modelpatient derived xenograft modelpreventprostate cancer modelprostate cancer progressionresponsetumortumor growth
项目摘要
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
癌细胞线粒体切换其代谢表型,以应对高能需求和
大分子合成。肿瘤对致癌酪氨酸激酶信号传导的急性依赖性支持其
然而,快速增殖是激酶活性与线粒体支持这些高能量的直接相关性
过程仍然晦涩难懂。偶然地,我们发现了一个非受体酪氨酸激酶ACK1,
在Tyr243和Tyr246(成熟蛋白质中的Tyr200&203),磷酸化ATP合酶F1α-盐酸(ATP5F1A)(ATP5F1A),
分别提高了在癌细胞中专门提高ATP合酶活性。从机械上讲,ATP5F1A-
磷酸化不仅排除了其与物理抑制剂ATPase抑制因子1(IF1)的结合,而且还包括
还创建了一个支撑结构,该结构从结合的非催化核苷酸延伸到表面,
降低柔韧性,从而提高酶的稳定性。新的ACK1抑制剂(R)-9B
逆转了这一过程,诱导了线粒体和减轻肿瘤的生长。一贯,明显增加
正常前列腺发展到恶性阶段,观察到ATP5F1A磷酸化。总体而言,这些
数据提供了癌细胞“线粒体成瘾”的分子证据,使Tyr-Kinase放纵和
揭示(R)-9b是损害癌细胞独特代谢需求的“ Mitocan”。
抑制前列腺癌(CRPC)仍然是无法治愈的恶性肿瘤,治疗方案有限,
是全球男性死亡的重要原因(15)。有限的效率和阻力快速发展
enzalutamide和abiraterone,AR拮抗剂治疗已建立了一种新的范式至现实的现实
缓解,其他特定癌症途径,包括代谢,必须妥协。该建议是指导的
详细表征ACK1/ATP5F1A的线粒体代谢调节特性
信号传导和检查(R)-9B克服enzalutamide和Abiraterone耐药的CRPC的能力。这
具体目的如下:
特定目的1。检查ATP5F1A-磷酸化调节其在前列腺活性的机制
癌症
具体目标2。探索ACK1/ATP5F1A信号在前列腺癌模型中的作用
特定目标3。恩扎拉胺和abiraterone-中ACK1/ATP5F1A信号传导的体内表征细节
前列腺癌和患者衍生Xenographtics(PDXS)的小鼠模型中的抗性
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nupam P Mahajan其他文献
Nupam P Mahajan的其他文献
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{{ truncateString('Nupam P Mahajan', 18)}}的其他基金
Targeting a Novel Signaling Nexus pACK/pCSK/pLCK in Immune Checkpoint Blockade (ICB)-Resistant Prostate Cancer
靶向新型信号转导 Nexus pACK/pCSK/pLCK 治疗免疫检查点阻断 (ICB) 耐药性前列腺癌
- 批准号:
10734202 - 财政年份:2023
- 资助金额:
$ 47.8万 - 项目类别:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7
- 批准号:
9977692 - 财政年份:2017
- 资助金额:
$ 47.8万 - 项目类别:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7
- 批准号:
9308352 - 财政年份:2017
- 资助金额:
$ 47.8万 - 项目类别:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7
- 批准号:
10112834 - 财政年份:2017
- 资助金额:
$ 47.8万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8082792 - 财政年份:2010
- 资助金额:
$ 47.8万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8460126 - 财政年份:2010
- 资助金额:
$ 47.8万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8246962 - 财政年份:2010
- 资助金额:
$ 47.8万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
7985538 - 财政年份:2010
- 资助金额:
$ 47.8万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8657844 - 财政年份:2010
- 资助金额:
$ 47.8万 - 项目类别:
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