Research Papers:

Targeting breast cancer metabolism with a novel inhibitor of mitochondrial ATP synthesis

Myoung Sook Kim _, Ramkishore Gernapudi, Yessenia Cedeño Cedeño, Brian M. Polster, Ramon Martinez, Paul Shapiro, Santosh Kesari, Elmar Nurmemmedov and Antonino Passaniti _

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Oncotarget. 2020; 11:3863-3885. https://doi.org/10.18632/oncotarget.27743

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Myoung Sook Kim1,3, Ramkishore Gernapudi2,3, Yessenia Cedeño Cedeño3, Brian M. Polster4,7, Ramon Martinez5, Paul Shapiro5, Santosh Kesari6, Elmar Nurmemmedov6 and Antonino Passaniti1,2,3,7

1 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA

2 Department of Biochemistry & Molecular Biology and Program in Molecular Medicine, Baltimore, MD, USA

3 The Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA

4 Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA

5 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

6 John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA

7 Research Health Scientist, The Veteran's Health Administration Research & Development Service (VAMHCS), Baltimore, MD, USA

Correspondence to:

Myoung Sook Kim,email: [email protected]
Antonino Passaniti,email: [email protected]

Keywords: mitochondrial ATP synthase; oxygen consumption rate; ATP synthesis; reactive oxygen species;

Received: July 28, 2020     Accepted: August 24, 2020     Published: October 27, 2020

Copyright: © 2020 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Inhibitors of mitochondrial respiration and ATP synthesis may promote the selective killing of respiration-competent cancer cells that are critical for tumor progression. We previously reported that CADD522, a small molecule inhibitor of the RUNX2 transcription factor, has potential for breast cancer treatment. In the current study, we show that CADD522 inhibits mitochondrial oxidative phosphorylation by decreasing the mitochondrial oxygen consumption rate (OCR) and ATP production in human breast cancer cells in a RUNX2-independent manner. The enzyme activity of mitochondrial ATP synthase was inhibited by CADD522 treatment. Importantly, results from cellular thermal shift assays that detect drug-induced protein stabilization revealed that CADD522 interacts with both α and β subunits of the F1-ATP synthase complex. Differential scanning fluorimetry also demonstrated interaction of α subunits of the F1-ATP synthase to CADD522. These results suggest that CADD522 might target the enzymatic F1 subunits in the ATP synthase complex. CADD522 increased the levels of intracellular reactive oxygen species (ROS), which was prevented by MitoQ, a mitochondria-targeted antioxidant, suggesting that cancer cells exposed to CADD522 may elevate ROS from mitochondria. CADD522-increased mitochondrial ROS levels were enhanced by exogenously added pro-oxidants such as hydrogen peroxide or tert-butyl hydroperoxide. Conversely, CADD522-mediated cell growth inhibition was blocked by N-acetyl-l-cysteine, a general ROS scavenger. Therefore, CADD522 may exert its antitumor activity by increasing mitochondrial driven cellular ROS levels. Collectively, our data suggest in vitro proof-of-concept that supports inhibition of mitochondrial ATP synthase and ROS generation as contributors to the effectiveness of CADD522 in suppression of tumor growth.

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