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

Oncotarget
Myoung Sook KimAntonino Passaniti

Abstract

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 R...Continue Reading

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Citations

Jul 2, 2021·Oncotarget·Annachiara MollaceNatalia Malara

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Methods Mentioned

BETA
gene knockdown
thermal shift
PCR
enzymatic assay
surface plasmon resonance
Assay

Software Mentioned

STATA
CETSA
GraphPad Prism

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