Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype

MnSOD-Ac-ROS-HIF2a 轴的失调促进 IR/顺铂耐药表型

• 批准号: 10024964
• 负责人: David Gius
• 金额: $ 7.28万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024964
• 关键词: Acetylation; Affect; Agar; Allografting; Biological Markers; Biology; Breast Cancer Cell; Cells; Cellular Metabolic Process; Chemical Exposure; Chemicals; Cisplatin; Complex; Data; Deacetylation; Drug Metabolic Detoxication; Enzymes; Equilibrium; Estrogen receptor positive; Event; Exhibits; Genetic; Genomic Instability; Growth; In Vitro; Ionizing radiation; Laboratories; Lysine; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Mus; Nature; Oncogenic; Peroxidases; Phenotype; Physiological; Property; Publications; Radiation exposure; Reactive Oxygen Species; Recurrence; Resistance; Role; SOD2 gene; Signal Transduction; Site; Subgroup; Superoxides; Tamoxifen; Therapeutic; Tumor Suppressor Proteins; Tumor stage; Work; Xenograft Model; Xenograft procedure; base; breast malignancies; density; high risk; in vivo; knock-down; mimetics; mitochondrial metabolism; mutant; neoplastic cell; new therapeutic target; novel; overexpression; prevent; radioresistant; stem cells; stem-like cell; stemness; therapy resistant; tissue/cell culture; tumor; tumor initiation; tumorigenesis; tumorigenic

Summary – The dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolism leads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling that disrupts metabolic balance, which can establish a tumorigenic and/or therapy resistant phenotype. In this regard, a subgroup of estrogen receptor-positive (ER+) breast malignancies, which exhibit increased ROS levels and a high risk of recurrence due to tamoxifen resistance (TamR), has been identified. We recently identified a novel mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cell metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, breast cancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2α (known to promote stemness-like properties), increased SOX2 and Oct4 (two established stem cell biomarkers), and displayed increased oncogenicity and TamR - implying that disruption of cell metabolism reprograms tumors to exhibit a stemness-like phenotype. Based on our new data, our recent publication (Zhu et al, Nature Commun. 2019), and work by others, it is hypothesized that dysregulated MnSOD biology, due to aberrant/increased MnSOD-K68-Ac levels, disrupts normal cellular and mitochondrial metabolism. This initiates metabolic reprogramming, via increased levels of HIF2α, leading to a cell stemness-mediated tumor-permissive and/or TamR phenotype.Thus, we seek to further explore how MnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype, leading to oncogenicity and/or TamR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic, reverse the oncogenic and/or TamR phenotypes?

综述-线粒体网络的失调是维持正常的原因 新陈代谢是癌症的一个公认的标志，也是肿瘤发生的早期事件。颠覆 细胞代谢障碍导致活性氧簇(ROS)积累并引发适应不良 破坏代谢平衡的信号，这可能建立起致癌和/或治疗耐药 表型。在这方面，雌激素受体阳性(ER+)乳腺癌的一个亚组， 由于对他莫昔芬的耐药性，表现出ROS水平升高和复发的高风险 (Tamr)，已被确认。我们最近发现了一个新的线粒体信号轴，它的中心是 锰超氧化物歧化酶(MnSOD)，当乙酰化(Ac)时赖氨酸的状态为68 (K68-Ac)改变，扰乱细胞新陈代谢，导致ROS水平异常(朱，自然通讯， 2019年)。此外，表达MnSOD-K68-Ac模拟突变体(MnSODK68Q)的乳腺癌细胞 表现出更高的HIF2α(已知可以促进茎状特性)，更高的SOX2和Oct4 (两个已建立的干细胞生物标志物)，并显示出更高的致瘤性和TAMR-暗示 细胞新陈代谢的中断使肿瘤重新编程，呈现出干细胞样的表型。基座 根据我们的新数据，我们最近的出版物(朱等人，《自然》)。2019年)，以及其他人的工作，它是 假设由于MnSOD-K68-Ac水平异常/增加， 扰乱正常的细胞和线粒体新陈代谢。这启动了新陈代谢重新编程，通过 HIF2α水平升高，导致细胞干细胞介导的肿瘤允许和/或TAMR 因此，我们试图进一步探索MnSOD-K68-Ac是如何扰乱细胞代谢和 促进类似茎的表型，导致致癌和/或TAMR。最后，GC4419是否会 暴露，一种化学的SOD解毒模拟，逆转致癌和/或TAMR表型？