细胞周期蛋白依赖性激酶4失活通过三阴性乳腺癌中线粒体-内质网接触重塑抑制细胞凋亡。

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

作者信息

Ziegler Dorian V, Parashar Kanishka, Leal-Esteban Lucia, López-Alcalá Jaime, Castro Wilson, Zanou Nadège, Martinez-Carreres Laia, Huber Katharina, Berney Xavier Pascal, Malagón María M, Roger Catherine, Berger Marie-Agnès, Gouriou Yves, Paone Giulia, Gallart-Ayala Hector, Sflomos George, Ronchi Carlos, Ivanisevic Julijana, Brisken Cathrin, Rieusset Jennifer, Irving Melita, Fajas Lluis

机构信息

Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland.

Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain.

出版信息

Nat Commun. 2025 Jan 9;16(1):541. doi: 10.1038/s41467-024-55605-z.

DOI:10.1038/s41467-024-55605-z

PMID:39788939

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11718081/

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.

摘要

肿瘤发生过程中增殖细胞的能量需求需要细胞周期与代谢之间的密切协调。虽然CDK4因其在细胞增殖中的作用而闻名，但其在癌症，尤其是三阴性乳腺癌（TNBC）中的代谢功能仍不清楚。我们的研究使用基因和药理学方法表明，CDK4失活仅对TNBC细胞增殖和肿瘤形成有适度影响。值得注意的是，CDK4缺失或长期抑制CDK4/6可使TNBC细胞对凋亡产生抗性。从机制上讲，CDK4增强线粒体-内质网接触（MERC）的形成，促进线粒体分裂和内质网-线粒体钙信号传导，这对TNBC的代谢灵活性至关重要。磷酸化蛋白质组分析确定了CDK4在MERC处调节PKA活性的作用。在这项工作中，我们强调了CDK4在抑制线粒体凋亡中的作用，并表明靶向与MERC相关的代谢转变可能会增强TNBC治疗效果。