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: 10737810
• 负责人: David Gius
• 金额: $ 6.81万
• 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/10737810
• 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

总结 这个新的R 01应用程序的首要目标是研究线粒体网络的失调 负责维持正常的新陈代谢是癌症的既定标志。这种细胞分裂 代谢，导致活性氧（ROS）的异常积累，引发适应不良 信号传导是导致电离辐射（IR）抗性（IRR）以及 恩杂鲁胺（ENZ）耐药（ENZR）。在这方面，最近确定了一个线粒体信号轴为中心， 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，破坏细胞代谢，导致异常的ROS水平（Zhu，Nature Commun.，2019年）。此外，本发明还提供了一种方法， 表达MnSOD K68-Ac模拟突变体（MnSODK 68 Q）的LNCaP细胞表现出IRR/ENZR，增加的HIF 2 α， 已知促进干细胞特性，和两个干细胞标记，Oct 4和SOX 2。因此，我们试图证明 MnSOD-K68-Ac可以通过改变MnSOD的结构组成和酶促活性来驱动IRR和/或ENZR， 活性，以及在更广泛的背景下，通过细胞干细胞样机制的肿瘤生长和存活。最后，Will GC 4419暴露，一种化学试剂，作为一个MnSOD模拟物，逆转IRR/ENZR表型？因此 假设暴露于IRR和/或ENZR的前列腺肿瘤细胞增加MnSOD-K68-Ac，破坏MnSOD-K68-Ac的活性。 在细胞和线粒体水平的正常MnSOD生物学（即，异常ROS），其启动细胞 通过增加HIF 2 α重编程，导致谱系可塑性，改变肿瘤细胞命运， IRR和/或ENZR肿瘤表型。MnSOD-K_（68）-Ac是一种新的治疗肿瘤的药物 IRR和IRR/ENZR肿瘤的干预。最后，通过接触GC 4419，化学取代 MnSOD活性，我们问是否超氧化物解毒逆转/转换这些IRR/ENZR前列腺肿瘤细胞 通过恢复正常的新陈代谢转化为敏感的表型