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

摘要 负责维持正常新陈代谢的线粒体网络失调是一种 癌症的明确标志和肿瘤发生的早期事件。细胞新陈代谢紊乱 导致活性氧(ROS)的积累，并触发适应不良的信号 破坏代谢平衡，从而形成致癌和/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，表现为 由于内分泌治疗，ROS水平升高和复发风险高，已被发现。 我们最近发现了一个新的以超氧化物锰为中心的线粒体信号轴 当赖氨酸68(K68-Ac)的乙酰化(Ac)状态改变时，歧化酶(MnSOD)会破坏 细胞代谢，导致ROS水平异常(朱，自然通讯，2019年)。此外，乳房 表达MnSODK68-Ac模拟突变体(MnSODK68Q)的癌细胞显示HIF2α增加 (已知可促进类茎特性)，增加SOX2和Oct4(两个已建立的干细胞 生物标志物)，导致致癌性和PAN耐药表型(PanR)通常 用于腔内B型乳腺恶性肿瘤--意味着细胞代谢的紊乱会使肿瘤重新编程 表现出谱系可塑性表型。基于我们的新数据，我们最近的出版物(朱等人， 自然界的普通人。2019年)，以及其他人的工作，它被假设为失调的MnSOD生物学， 由于MnSOD-K68-Ac水平异常/增加，扰乱正常细胞和线粒体 新陈代谢。这通过增加HIF2α的水平启动新陈代谢重新编程，导致细胞 干细胞介导的肿瘤允许和/或PanR表型。因此，我们寻求进一步探索如何 MnSOD-K68-Ac扰乱细胞新陈代谢，促进茎样表型，导致 致瘤性和/或PANR。最后，将GC4419暴露，模拟一种化学的超氧化物歧化酶解毒， 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?