CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer

Dorian V. Ziegler, Kanishka Parashar, Lucia Leal-Esteban, Jaime López-Alcalá, Wilson Castro, Nadège Zanou, Laia Martinez-Carreres, Katharina Huber, Xavier Pascal Berney, María M. Malagón, Catherine Roger, Marie-Agnès Berger, Yves Gouriou, Giulia Paone, Hector Gallart-Ayala, George Sflomos, Carlos Ronchi, Julijana Ivanisevic, Cathrin Brisken, Jennifer Rieusset, Melita Irving and Lluis Fajas ()
Additional contact information
Dorian V. Ziegler: Faculty of Biology and Medicine
Kanishka Parashar: Faculty of Biology and Medicine
Lucia Leal-Esteban: Faculty of Biology and Medicine
Jaime López-Alcalá: Faculty of Biology and Medicine
Wilson Castro: Faculty of Biology and Medicine
Nadège Zanou: Faculty of Biology and Medicine
Laia Martinez-Carreres: Faculty of Biology and Medicine
Katharina Huber: Faculty of Biology and Medicine
Xavier Pascal Berney: Faculty of Biology and Medicine
María M. Malagón: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital
Catherine Roger: Faculty of Biology and Medicine
Marie-Agnès Berger: Université Claude Bernard Lyon1
Yves Gouriou: Université Claude Bernard Lyon1
Giulia Paone: Faculty of Biology and Medicine
Hector Gallart-Ayala: Faculty of Biology and Medicine
George Sflomos: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Carlos Ronchi: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Julijana Ivanisevic: Faculty of Biology and Medicine
Cathrin Brisken: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Jennifer Rieusset: Université Claude Bernard Lyon1
Melita Irving: Faculty of Biology and Medicine
Lluis Fajas: Faculty of Biology and Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-55605-z

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