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

摘要 这一新的R01应用程序的首要目标是研究线粒体网络的失调 负责维持正常新陈代谢是癌症的既定标志。这种对细胞的破坏 新陈代谢，导致活性氧物种(ROS)的异常积累，引发适应不良 信号是一种导致电离辐射(IR)抵抗(IRR)以及 苯扎鲁胺(ENZ)耐药性(ENZR)。在这方面，最近发现了一个以线粒体信号轴为中心的 关于赖氨酸68(K68-Ac)乙酰化(Ac)状态的锰超氧化物歧化酶(MnSOD) 改变，扰乱细胞新陈代谢，导致ROS水平异常(朱，自然通讯，2019)。此外, 表达MnSODK68-Ac模拟突变体(MnSODK68Q)的LNCaP细胞表现出IRR/ENZR，HIF2α增加， 已知可以促进茎的特性，以及两个干细胞标记，Oct4和SOX2。因此，我们试图展示 MnSOD-K68-Ac可能通过改变MnSOD的结构组成和酶活性来驱动IRR和/或ENZR 在更广泛的背景下，通过细胞干细胞样机制，肿瘤的生长和存活。最后，威尔 GC4419暴露，一种模拟MnSOD的化学试剂，是否逆转IRR/ENZR表型？因此，它 是否假设暴露于IRR和/或ENZR的前列腺肿瘤细胞增加MnSOD-K68-Ac，破坏 在细胞和线粒体水平上的正常MnSOD生物学(即，异常的ROS)，它启动了细胞 通过增加HIF2α重新编程，导致谱系可塑性特性，改变肿瘤细胞命运，以及 IRR和/或ENZR肿瘤表型。还提出了MnSOD-K68-Ac是一种新的治疗方法 对IRR和IRR/ENZR肿瘤的干预。最后，通过接触GC4419，化学上取代了 MnSOD活性，我们询问超氧化物歧化是否能逆转/转化这些IRR/ENZR前列腺癌细胞 通过恢复正常新陈代谢转变为敏感的表型