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 HIF2? (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 HIF2?, 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?
We have identified a mitochondrial signaling axis centered on MnSOD-K68 which, when its normal acetylation status is altered, disrupts cell metabolism, leading to aberrant-ROS levels, and a tumor permissive phenotype (Zhu et al, 2019). Interestingly, emerging data suggests that the disruption of mitochondrial metabolism, including aberrant ROS levels, is an increasingly accepted mechanism of oncogenicity due to an enrichment of stem-like cells. Thus, it is proposed that when MnSOD-Ac exists outside of its normal physiological context, it disrupts cellular and mitochondrial metabolism and promotes lineage plasticity properties (or tumor cell stemness), leading to an oncogenic permissive and TamR phenotype, and is a potential target for new therapies.
