CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer
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...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55605-z |
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| author | 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 Lluis Fajas |
| author_facet | 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 Lluis Fajas |
| author_sort | Dorian V. Ziegler |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b375f83e71b8478aa0b895a1b114bfdc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b375f83e71b8478aa0b895a1b114bfdc2025-01-12T12:31:24ZengNature PortfolioNature Communications2041-17232025-01-0116112310.1038/s41467-024-55605-zCDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancerDorian V. Ziegler0Kanishka Parashar1Lucia Leal-Esteban2Jaime López-Alcalá3Wilson Castro4Nadège Zanou5Laia Martinez-Carreres6Katharina Huber7Xavier Pascal Berney8María M. Malagón9Catherine Roger10Marie-Agnès Berger11Yves Gouriou12Giulia Paone13Hector Gallart-Ayala14George Sflomos15Carlos Ronchi16Julijana Ivanisevic17Cathrin Brisken18Jennifer Rieusset19Melita Irving20Lluis Fajas21Center for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineLudwig Institute for Cancer Research, University of Lausanne, Faculty of Biology and MedicineInstitute of Sport Sciences and Department of Biomedical Sciences, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineDepartment of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University HospitalCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineLaboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1Center for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineMetabolomics Platform, University of Lausanne, Faculty of Biology and MedicineISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)Metabolomics Platform, University of Lausanne, Faculty of Biology and MedicineISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1Ludwig Institute for Cancer Research, University of Lausanne, Faculty of Biology and MedicineCenter for Integrative Genomics, University of Lausanne, Faculty of Biology and MedicineAbstract 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.https://doi.org/10.1038/s41467-024-55605-z |
| spellingShingle | 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 Lluis Fajas CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer Nature Communications |
| title | CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer |
| title_full | CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer |
| title_fullStr | CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer |
| title_full_unstemmed | CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer |
| title_short | CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer |
| title_sort | cdk4 inactivation inhibits apoptosis via mitochondria er contact remodeling in triple negative breast cancer |
| url | https://doi.org/10.1038/s41467-024-55605-z |
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