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?

摘要 - 线粒体网络的失调，负责保持正常 代谢是癌症的既定标志，也是肿瘤发生的早期事件。破坏 细胞代谢导致活性氧（ROS）和触发不良适应性的积累 信号会破坏代谢平衡，这可以建立抗肿瘤和/或抗治疗 表型。在这方面，雌激素受体阳性（ER+）乳腺癌的亚组， 暴露于他莫昔芬耐药性引起的ROS水平和高风险 （TAMR）已被鉴定。我们最近确定了一个以上为中心的新型线粒体信号轴 当赖氨酸的乙酰化（AC）状态68时 （K68-AC）被改变，破坏细胞代谢，导致异常ROS水平（Zhu，Nature Commun。 2019）。此外，表达MNSOD-K68-AC模拟突变体的乳腺癌细胞（MNSODK68Q） 暴露的HIF2α增加（已知会促进类似干性的特性），Sox2和Oct4增加 （两个已建立的干细胞生物标志物），并表现出增加的致癌性和TAMR 细胞代谢的破坏重新编程以退出类似干性的表型。基于 关于我们的新数据，我们最近的出版物（Zhu等人，自然界，2019年），以及其他人的工作，这是 假设由于异常/MNSOD-K68-AC水平增加，MNSOD生物学失调， 破坏正常的细胞和线粒体代谢。这会启动代谢重编程，通过 HIF2α的水平升高，导致细胞干介导的肿瘤 - 验证和/或TAMR 表型。因此，我们寻求进一步探索MNSOD-K68-AC如何破坏细胞代谢和 促进类似干性的表型，导致致癌性和/或TAMR。最后，将GC4419 暴露，一种化学SOD解毒模仿，逆转致癌和/或TAMR表型？