Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

Frontiers in Pharmacology · 14 authors, 5 centres

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TL;DR

This preclinical study used a multi-omics approach on triple-negative breast cancer cells to show that the ClpP activators ONC201 and TR-57 cause highly similar, ClpP-dependent disruptions to mitochondrial proteins, transcripts, and metabolites.

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This preclinical in vitro study used mass spectrometry-based proteomics, transcriptomics, and metabolomics to characterize the effects of ClpP activators ONC201 and TR-57 on SUM159 triple-negative breast cancer cells. After 24-hour treatment, both compounds induced highly similar ClpP-dependent changes, including the downregulation of hundreds of mitochondrial proteins and transcripts involved in processes like mitochondrial translation and the TCA cycle. The analysis identified perturbed pathways including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. The findings support a model where ClpP activation broadly disrupts mitochondrial function required for cancer cell proliferation.

STUDY TYPE

other

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10103842

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

Frontiers in Pharmacology

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ABSTRACT

ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

CITATION EXPORT

Emily M. J. Fennell, Lucas J. Aponte-Collazo, Wimal Pathmasiri et al.. Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer. Frontiers in Pharmacology. (2023). https://doi.org/10.3389/fphar.2023.1136317

AUTHORS

14 · 5 CENTRES

Emily M. J. Fennell, Lucas J. Aponte-Collazo, Wimal Pathmasiri, Blake R. Rushing, Natalie K. Barker, Megan C. Partridge, Yuan-Yuan Li, Cody A. White, Yoshimi E. Greer, Laura E. Herring, Stanley Lipkowitz, Susan C. J. Sumner, Edwin J. Iwanowicz, Lee M. Graves

1 Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
2 Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
3 Michael Hooker Proteomics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
4 Women’s Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
5 Madera Therapeutics, LLC, Cary, NC, United States