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: 10390451
• 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/10390451
• 关键词: Acetylation; Allografting; Antioxidants; Appearance; Biology; Cells; Cellular Metabolic Process; ChIP-seq; Chemical Agents; Chemicals; Clinical; Clinical Research; 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; Plant Roots; Process; Property; Prostate; Proteins; Reactive Oxygen Species; Reporter; Research; Resistance; Role; SOD2 gene; Signal Transduction; Superoxides; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Recombination; Tumor Suppressor Proteins; androgen deprivation therapy; base; enzalutamide; high risk; in vivo; in vivo Model; knock-down; men; mitochondrial metabolism; molecular marker; 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 该新的R01应用程序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既定标志。 代谢，导致活性氧（ROS）的异常积累，触发适应不良 信号传导是一种新兴的新型机制，导致电离辐射（IR）电阻（IRR）以及 在这方面，enzalutamide（ENZ）电阻（ENZR）。 关于锰超氧化物歧化酶（MNSOD），当赖氨酸68（K68-AC）的乙酰化（AC）状态为 改变，破坏了细胞代谢，导致异常ROS水平（Zhu，Nature Commun。，2019年）。 表达MNSOD K68-AC模拟突变体（MNSODK68Q）的LNCAP细胞表现出IRR/ENZR，增加了HIF2α，增加 已知的茎性特性和两个干细胞标记，OCT4和SOX2。 通过更改MNSOD的结构组成和酶促的，MNSOD-K68-AC可能会驱动IRR ARR和/或ENZR 活性，以及​​在更广泛的环境中，通过类似细胞的机制的肿瘤生长和存活。 GC4419暴露是一种化学物质的MNSOD模拟物，逆转了IRR/ENZR表型 假设暴露于IRR和/或ENZR的前列腺肿瘤细胞增加了MNSOD-K68-AC，破坏了 正常的MnSOD生物学在细胞和米孔室水平（即异常ROS）处，启动细胞 通过增加的HIF2α，将其录音仪导致谱系塑性特性，肿瘤细胞命运的变化和A IRR和/或ENZR肿瘤表型。 IRR和IRN/ENZR肿瘤的干预措施，尽管暴露于GC4419 MNSOD活性，我们询问超氧化排毒是否恢复/转换这些IR/ENZR前列腺肿瘤细胞 通过恢复正常代谢来敏感表型