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

摘要-负责维持正常的线粒体网络失调 代谢是癌症的既定标志和肿瘤发生的早期事件。中断 细胞代谢的失调导致活性氧簇（ROS）的积累并引发适应不良 破坏代谢平衡的信号传导，这可以建立致瘤性和/或治疗抗性。 表型。在这方面，雌激素受体阳性（ER+）乳腺恶性肿瘤的亚组， 其表现出增加的ROS水平和由于他莫昔芬耐药性引起的高复发风险 （TamR）已被识别。我们最近发现了一种新的线粒体信号轴， 锰超氧化物歧化酶（MnSOD），当赖氨酸68的乙酰化（Ac）状态 （K68-Ac）改变，破坏细胞代谢，导致异常的ROS水平（Zhu，Nature Commun.， 2019年）。此外，表达MnSOD-K68-Ac模拟突变体（MnSODK 68 Q）的乳腺癌细胞 表现出增加的HIF 2 α（已知促进干细胞样特性），增加的SOX 2和Oct 4 (two已建立的干细胞生物标志物），并显示出致癌性和TamR增加，这意味着 细胞代谢的破坏使肿瘤重新编程，表现出干细胞样表型。基于 根据我们的新数据，我们最近的出版物（Zhu等人，Nature Commun. 2019），和其他人的工作，它是 假设由于MnSOD-K68-Ac水平的异常/增加， 破坏正常的细胞和线粒体代谢。这启动了代谢重编程，通过 HIF 2 α水平升高，导致细胞干细胞介导的肿瘤容许和/或TamR 因此，我们寻求进一步探索MnSOD-K68-Ac如何破坏细胞代谢， 促进干细胞样表型，导致致癌性和/或TamR。第4419章 暴露，一种化学SOD解毒模拟物，逆转致癌和/或TamR表型？

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?