CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
Details
Serval ID
serval:BIB_C59FE7AA0BFC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
Journal
Nature communications
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
09/01/2025
Peer-reviewed
Oui
Volume
16
Number
1
Pages
541
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
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.
Keywords
Triple Negative Breast Neoplasms/metabolism, Triple Negative Breast Neoplasms/pathology, Triple Negative Breast Neoplasms/genetics, Humans, Apoptosis/drug effects, Mitochondria/metabolism, Female, Cyclin-Dependent Kinase 4/metabolism, Cyclin-Dependent Kinase 4/genetics, Cell Line, Tumor, Animals, Cell Proliferation/drug effects, Mitochondrial Dynamics/drug effects, Endoplasmic Reticulum/metabolism, Mice, Cyclic AMP-Dependent Protein Kinases/metabolism, Cyclic AMP-Dependent Protein Kinases/genetics, Calcium Signaling
Pubmed
Open Access
Yes
Create date
17/01/2025 9:46
Last modification date
24/01/2025 7:05