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

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $72,799

## Abstract

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?

## Key facts

- **NIH application ID:** 10024964
- **Project number:** 3R01CA214025-04S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David Gius
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,799
- **Award type:** 3
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024964

## Citation

> US National Institutes of Health, RePORTER application 10024964, Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype (3R01CA214025-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10024964. Licensed CC0.

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