Journal Article

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

Leal-Esteban, Lucia, López-Alcalá, Jaime, Ziegler, Dorian, Paone, Giulia, Fajas, Lluis, Berney, Xavier Pascal, Castro, Wilson, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sflomos, George, Brisken, Cathrin, Ronchi, Carlos, Malagón, María, Irving, Melita, Gouriou, Yves, Berger, Marie-Agnès, Parashar, Kanishka, Zanou, Nadège, Gallart-Ayala, Hector, Ivanisevic, Julijana, Rieusset, J, Roger, Catherine, Martinez-Carreres, Laia, Huber, Katharina

2025

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio
• Subject: 13 / 13/106 / 13/109 / 13/2 / 13/44 / 13/95 / 14/1 / 14/19 / 14/28 / 14/5 / 38 / 38/91 / 631/67 / 631/67/1347 / 631/67/2327 / 64/60 / 82/58 / 82/80 / Animals / Apoptosis / Apoptosis - drug effects / Breast cancer / Calcium (mitochondrial) / Calcium Signaling / Calcium signalling / Cell cycle / Cell growth / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cyclic AMP-Dependent Protein Kinases - genetics / Cyclic AMP-Dependent Protein Kinases - metabolism / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - genetics / Cyclin-Dependent Kinase 4 - metabolism / Deactivation / Endoplasmic reticulum / Endoplasmic Reticulum - metabolism / Female / Humanities and Social Sciences / Humans / Life Sciences / Metabolism / Mice / Mitochondria / Mitochondria - metabolism / Mitochondrial Dynamics - drug effects / multidisciplinary / Science / Science (multidisciplinary) / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Tumorigenesis
• ISBN: 0013950283000