<scp>BET</scp> inhibitors (<scp>BETi</scp>) influence oxidative phosphorylation metabolism by affecting mitochondrial dynamics leading to alterations in apoptotic pathways in triple‐negative breast cancer (<scp>TNBC</scp>) cells
Repressing BET proteins' function using bromodomain inhibitors (BETi) has been shown to elicit antitumor effects by regulating the transcription of genes downstream of BRD4. We previously showed that BETi promoted cell death of triple-negative breast cancer (TNBC) cells. Here, we proved that BETi induce altered mitochondrial dynamics fitness in TNBC cells falling in cell death. We demonstrated that BETi treatment downregulated the expression of BCL-2, and proteins involved in mitochondrial fission and increased fused mitochondria. Impaired mitochondrial fission affected oxidative phosphorylation (OXPHOS) inducing the expression of OXPHOS-related genes, SDHa and ATP5a, and increased cell death. Consistently, the amount of mitochondrial DNA and mitochondrial membrane potential (∆Ψm) increased in BETi-treated cells compared to control cells. Lastly, BETi in combination with Metformin reduced cell growth. Our results indicate that mitochondrial dynamics and OXPHOS metabolism support breast cancer proliferation and represent novel BETi downstream targets in TNBC cells.
Authors
- Maria Eugenia Gallo Cantafio (ORCID: https://orcid.org/0009-0009-9937-0565)
- Mattea Chirico (ORCID: https://orcid.org/0000-0002-3447-5077)
- Alessia Ciarrocchi (ORCID: https://orcid.org/0000-0002-5541-2075)
- Noemi Puccio (ORCID: https://orcid.org/0000-0002-1016-3597)
- Mariaelena Pistoni (ORCID: https://orcid.org/0000-0002-1219-0038)
- Antonino Neri (ORCID: https://orcid.org/0000-0001-9047-5912)
- Marco Fiorillo (ORCID: https://orcid.org/0000-0002-8055-3259)
- Egidio Iorio (ORCID: https://orcid.org/0000-0001-6673-3838)
- Francesca Colciaghi (ORCID: https://orcid.org/0000-0002-6487-380X)
- Maria Elena Pisanu (ORCID: https://orcid.org/0000-0002-0029-3523)
- Ida Perrotta (ORCID: https://orcid.org/0000-0002-9061-9776)
- Teresa Rossi (ORCID: https://orcid.org/0000-0002-0426-7197)
- Nicola Amodio (ORCID: https://orcid.org/0000-0002-1345-4410)
- Alessia Gianferrari
Institutions
- Istituto Superiore di Sanità (IT)
- Magna Graecia University (IT)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- University of Calabria (IT)
Publication Details
- Journal
- Cell Proliferation
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1111/cpr.13730
- Citations
- 13
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro