CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer
The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.
Authors
- Nadège Zanou (ORCID: https://orcid.org/0000-0001-6626-3127)
- Lluís Fajas (ORCID: https://orcid.org/0000-0002-1283-9503)
- Dorian V. Ziegler (ORCID: https://orcid.org/0000-0002-0475-6353)
- Jaime López‐Alcalá (ORCID: https://orcid.org/0000-0001-5843-669X)
- Marı́a M. Malagón (ORCID: https://orcid.org/0000-0002-2419-2727)
- Kanishka Parashar (ORCID: https://orcid.org/0000-0002-3211-6767)
- Jennifer Rieusset (ORCID: https://orcid.org/0000-0002-1587-2253)
- Katharina Huber (ORCID: https://orcid.org/0000-0002-4072-4877)
- Carlos Ronchi (ORCID: https://orcid.org/0000-0002-8079-8643)
- Catherine Roger
- Marie-Agnès Berger (ORCID: https://orcid.org/0000-0003-4189-6029)
- Melita Irving (ORCID: https://orcid.org/0000-0002-6849-7194)
- George Sflomos (ORCID: https://orcid.org/0000-0003-2972-0549)
- Laia Martínez-Carreres (ORCID: https://orcid.org/0000-0002-5685-094X)
- Lucía C. Leal-Esteban (ORCID: https://orcid.org/0000-0002-3618-8346)
- Xavier Berney
- Yves Gouriou (ORCID: https://orcid.org/0000-0003-2565-4935)
- Cathrin Brisken (ORCID: https://orcid.org/0000-0002-6857-3230)
- Julijana Ivanišević (ORCID: https://orcid.org/0000-0001-8267-2705)
- Wilson Castro (ORCID: https://orcid.org/0000-0002-9649-9883)
- Héctor Gallart‐Ayala (ORCID: https://orcid.org/0000-0003-2333-0646)
- G Paone
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Institute of Cancer Research (GB)
- Inserm (FR)
- Breast Cancer Now (GB)
- Instituto de Salud Carlos III (ES)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Hospices Civils de Lyon (FR)
- Délégation Régionale Occitanie Méditerranée (FR)
- Centro de Investigación Biomédica en Red (ES)
- Ludwig Cancer Research (CH)
- Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition (FR)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Córdoba (ES)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1038/s41467-024-55605-z
- Citations
- 7
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- National Science Foundation
- European Molecular Biology Organization
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Austrian Science Fund
- Ministerio de Ciencia e Innovación
- Université de Lausanne
- Fondation ISREC