MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies

总结 负责维持正常代谢的线粒体网络的失调是一种 癌症的标志和肿瘤发生的早期事件。细胞新陈代谢的中断 导致活性氧（ROS）的积累并触发适应不良信号， 破坏代谢平衡，这可以建立肿瘤发生和/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，其表现为： 已经确定了内分泌治疗引起的ROS水平增加和复发的高风险。 我们最近发现了一个新的线粒体信号轴为中心的锰超氧化物 当赖氨酸68（K68-Ac）的乙酰化（Ac）状态改变时， 细胞代谢，导致异常的ROS水平（Zhu，Nature Commun.，2019年）。此外，乳房 表达MnSOD-K68-Ac模拟突变体（MnSODK 68 Q）的癌细胞显示HIF 2 α表达增加， （已知促进干细胞样特性），增加SOX 2和Oct 4（两种已建立的干细胞 生物标志物），导致致瘤性和泛耐药表型（PanR）的药物通常 用于管腔型B乳腺癌--这意味着细胞代谢的破坏会重新编程肿瘤 表现出谱系可塑性表型。根据我们的新数据，我们最近的出版物（Zhu et al， 自然通讯2019），以及其他人的工作，假设MnSOD生物学失调， 由于MnSOD-K68-Ac水平异常/增加，破坏正常细胞和线粒体 新陈代谢.这通过增加HIF 2 α水平启动代谢重编程，导致细胞 干细胞介导的肿瘤容许和/或PanR表型。因此，我们寻求进一步探讨如何 MnSOD-K68-Ac破坏细胞代谢并促进干细胞样表型，导致 致癌性和/或PanR。最后，将GC 4419暴露，一种化学SOD解毒模拟物， 逆转致癌和/或PanR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 endocrine therapy, has been identified. We recently found 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), leading to oncogenicity and pan resistance phenotype (PanR) to agents commonly used in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumors to exhibit a lineage plasticity 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 PanR 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 PanR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic, reverse the oncogenic and/or PanR phenotypes?