Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy

由于 MnSOD 生物学的破坏，谱系可塑性驱动了对电离辐射/雄激素剥夺疗法的抵抗

• 批准号: 10548835
• 负责人: David Gius
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548835
• 关键词: Acetylation; Allografting; Antioxidants; Appearance; Biology; Cells; Cellular Metabolic Process; ChIP-seq; Chemical Agents; Chemicals; Clinical; Clinical Research; Compensation; Complex; Data; Development; Drug Metabolic Detoxication; Exhibits; Exposure to; Genes; Genetic; Goals; Grant; Growth; In Vitro; Ionizing radiation; LNCaP; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular Target; Nature; Organoids; Paper; Peroxidases; Phenotype; Process; Property; Prostate; Proteins; Reactive Oxygen Species; Recurrence; Reporter; Research; Resistance; Role; SOD2 gene; Signal Transduction; Superoxides; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Recombination; Tumor Suppressor Proteins; androgen deprivation therapy; enzalutamide; high risk; in vivo; in vivo Model; knock-down; men; mitochondrial metabolism; molecular marker; monomer; mouse model; mutant; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; patient derived xenograft model; prostate cancer cell; radiation resistance; stem cell biomarkers; stem-like cell; stemness; therapy resistant; tissue culture; transcriptome sequencing; tumor; tumor growth; vector

SUMMARY The overarching goal of this new R01 application is to investigate the dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer. This disruption of cellular metabolism, leads to the aberrant accumulation of reactive oxygen species (ROS), triggering maladaptive signaling that is an emerging, novel mechanism leading to ionizing radiation (IR) resistance (IRR) as well as enzalutamide (ENZ) resistance (ENZR). In this regard, recently identified a mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cellular metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, LNCaP cells expressing a MnSOD K68-Ac mimic mutant (MnSODK68Q) exhibited IRR/ENZR, increased HIF2α, known to promote stemness properties, and two stem cell markers, Oct4 and SOX2. As such, we seek to show that MnSOD-K68-Ac may drive IRR and/or ENZR, by altering MnSOD's structural composition and enzymatic activity, and in a broader context, tumor growth and survival via a cell stemness-like mechanism. Finally, will GC4419 exposure, a chemical agent that acts as a MnSOD mimic, reverse the IRR/ENZR phenotype? Thus, it is It is hypothesized that prostate tumor cells exposed to IRR and/or ENZR increase MnSOD-K68-Ac, disrupting normal MnSOD biology at the cellular and mitochondrial level (i.e., aberrant ROS), which initiates cellular reprogramming, via increased HIF2α, leading to lineage plasticity properties, a change in tumor cell fate, and an IRR and/or ENZR tumor phenotype. It is also proposed that MnSOD-K68-Ac is a novel axis for new therapeutic interventions in IRR and IRR/ENZR tumors. Finally, through exposure to GC4419 that chemically replaces MnSOD activity, we ask whether superoxide detoxification reverts/converts these IRR/ENZR prostate tumor cells to a sensitive phenotype by restoring normal metabolism

概括 这一新 R01 应用的总体目标是研究线粒体网络的失调 负责维持正常代谢是癌症的一个既定标志。 新陈代谢，导致活性氧（ROS）异常积累，引发适应不良 信号传导是一种新兴的新颖机制，可导致电离辐射 (IR) 抗性 (IRR) 以及 在这方面，最近发现了以线粒体信号轴为中心的恩杂鲁胺（ENZ）耐药性（ENZR）。 对锰超氧化物歧化酶 (MnSOD) 的影响，当赖氨酸 68 (K68-Ac) 的乙酰化 (Ac) 状态为 改变，扰乱细胞代谢，导致 ROS 水平异常（Zhu，Nature Commun.，2019）。 表达 MnSOD K68-Ac 模拟突变体 (MnSODK68Q) 的 LNCaP 细胞表现出 IRR/ENZR、HIF2α 增加、 已知可促进干性特性，以及两个干细胞标记，Oct4 和 SOX2。因此，我们试图证明。 MnSOD-K68-Ac 可能通过改变 MnSOD 的结构组成和酶促作用来驱动 IRR 和/或 ENZR 活性，以及​​在更广泛的背景下，通过类似细胞干细胞机制的肿瘤生长和存活。 GC4419 暴露是一种充当 MnSOD 模拟物的化学制剂，可以逆转 IRR/ENZR 表型吗？ 据报道，暴露于 IRR 和/或 ENZR 的前列腺肿瘤细胞会增加 MnSOD-K68-Ac，破坏 细胞和线粒体水平上的正常 MnSOD 生物学（即异常 ROS），启动细胞 通过增加 HIF2α 进行重编程，导致谱系可塑性、肿瘤细胞命运的改变以及 IRR 和/或 ENZR 肿瘤表型还提出 MnSOD-K68-Ac 是新治疗的新轴。 最后，通过接触化学替代的 GC4419 来干预 IRR 和 IRR/ENZR 肿瘤。 MnSOD 活性，我们询问超氧化物解毒是否会恢复/转化这些 IRR/ENZR 前列腺肿瘤细胞 通过恢复正常代谢来达到敏感表型