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

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $390,240

## Abstract

Summary - Metabolic stress, a hallmark of cancer, is an early event in tumorigenesis that
accumulates in the cell from endogenous processes, exogenous conditions, and/or agents that
induce oxidative stress. Additionally, the aberrant accumulation of reactive oxygen species (ROS),
as well as altered mitochondrial metabolism (i.e., oxidative or metabolic stress), are early events in
the process of cellular reprogramming that under specific conditions leads to tumor cell resistance.
It has become increasingly clear that lysine acetylation (i.e., mitochondrial Acetylome) is the
primary post-translational modification employed by the mitochondrial to sense changes in ROS
and/or metabolic conditions and initial adaptive or reparative signaling processes, including
metabolic reprogramming to maintain homeostatic poise. While a link between the dysregulation of
the mitochondrial Acetylome, ROS detoxification (i.e., metabolic stress), and metabolic
reprogramming leading to tumor cell resistance has long been suggested, rigorous mechanistic
data to supporting this intriguing idea has been limited. In this grant application it is proposed that
the acetylation status of manganese superoxide dismutase (MnSOD), a critical mitochondrial
enzyme, directs detoxification activity as well as connects metabolic stress and mitochondrial
reparative pathways that maintain metabolic fidelity. In this regard, it is proposed that MnSOD
exhibits a dichotomous function, based on the acetylation status of K68, where the homotetrameric
form acts as a protective detoxification enzyme against aberrant ROS levels. In contrast, K68
acetylation inhibits the homotetrameric complex and MnSOD subsequently forms a monomeric
protein form that is proposed to function as an oncoprotein. Thus, it is proposed that the
dysregulation MnSOD axis, due to acetylation, alters MnSOD function which subsequently
reprograms mitochondria resulting in a tumor cell anti-cancer resistance therapy phenotype. In
addition, targeted the acetylation status or restoring the MnSOD functions will be used to generate
and validation of new therapeutic strategies to sensitize tumor cells to cytotoxic therapies

## Key facts

- **NIH application ID:** 9889066
- **Project number:** 5R01CA214025-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David Gius
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,240
- **Award type:** 5
- **Project period:** 2017-04-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889066

## Citation

> US National Institutes of Health, RePORTER application 9889066, Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype (5R01CA214025-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9889066. Licensed CC0.

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