# Role of succinate dehydrogenase in ovarian cancer metabolism

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2022 · $349,600

## Abstract

Chemotherapy-resistant ovarian cancer recurs in ~85% of patients and contributes to high rates of cancer-related
mortality. The reprograming of cellular metabolism towards anaerobic glycolysis (the Warburg effect) is an
important mechanism of chemotherapy resistance. Precision medicine targeting the unique metabolic state of
cancer holds great promise to improve the efficacy of ovarian cancer treatment and reduce chemotherapy
resistance. From a comprehensive analysis of metabolic pathways in our patient-derived ovarian tumors and
The Cancer Genome Atlas (TCGA) data, we discovered that a key mitochondrial enzyme, succinate
dehydrogenase (SDHA), is significantly upregulated in 19% of ovarian cancer patients, and is associated with
significantly improved patient survival. Our preliminary studies indicate that elevated SDHA increases
mitochondrial pyruvate carrier 1 (MPC1) protein expression, which increases pyruvate import to mitochondrial
leading to reversal of the Warburg effect and suppression of cell proliferation. In addition, our preliminary data
shows that elevated SDHA contributes to imbalance of redox systems, which may sensitize ovarian cancer cells
to chemotherapy and/or agents that generate reactive oxygen species (ROS). The overall goal of this study
is to determine the mechanism by which elevated SDHA alters ovarian tumor biology to take full advantage of
druggable metabolic vulnerabilities such as increased sensitivity to chemotherapy and/or ROS-generating
agents to improve patient survival. In Aim 1, we will determine the mechanism by which elevated SDHA
reprograms cellular metabolism to regulate ovarian cancer cell proliferation. We will overexpress or knockdown
SDHA in ovarian cancer cell lines followed by metabolic and functional characterization of the cells including an
evaluation of glycolysis, oxygen consumption and pyruvate transport into mitochondria by Seahorse XF
Technology, mass spectrometry and metabolic tracer analyses. We will explore the independent roles of
elevated SDHA, SDHA substrates (succinate, fumarate), or MPC1 in reprograming of cellular metabolism and
cell proliferation. In Aim 2, we will determine if elevated SDHA, by impairing cellular redox regulation, increases
ovarian tumor sensitivity to chemotherapy (cisplatin/paclitaxel) and/or a ROS-generating agent (elesclomol). We
will test the effect of SDHA on increasing mitochondrial-dependent respiration and ROS generation by
performing respirometry analyses. Finally, we will test in vivo if SDHA-amplified ovarian tumors show better
responses to chemotherapy and/or elesclomol using selected patient-derived xenografts (PDXs). The
immediate contribution of this project is to explore the novel role of SDHA in changing mitochondrial energy
metabolism to improve ovarian cancer patient survival by suppressing of tumor growth and/or increasing the
effectiveness of chemotherapy to kill tumor cells. This study is a critical step toward our long-term goal, to
develop in...

## Key facts

- **NIH application ID:** 10339352
- **Project number:** 5P20GM139763-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Magdalena Bieniasz
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,600
- **Award type:** 5
- **Project period:** 2021-02-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339352

## Citation

> US National Institutes of Health, RePORTER application 10339352, Role of succinate dehydrogenase in ovarian cancer metabolism (5P20GM139763-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10339352. Licensed CC0.

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