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CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer
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CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer
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Journal Article
CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer
2025
Overview
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.
CDK4/6 inhibitors (CDK4/6i) have improved cancer patient outcomes but shown limited benefits for those with triple-negative breast cancer (TNBC). Here, the authors report that CDK4/6 inhibition prevents CDK4 enhanced mitochondria-endoplasmic reticulum interactions, inhibiting mitochondrial apoptosis and driving resistance to CDK4/6i in TNBC models.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 14/5
/ 38
/ 38/91
/ 631/67
/ 64/60
/ 82/58
/ 82/80
/ Animals
/ Cell Proliferation - drug effects
/ Cyclic AMP-Dependent Protein Kinases - genetics
/ Cyclic AMP-Dependent Protein Kinases - metabolism
/ Cyclin-Dependent Kinase 4 - genetics
/ Cyclin-Dependent Kinase 4 - metabolism
/ Endoplasmic Reticulum - metabolism
/ Female
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Mitochondrial Dynamics - drug effects
/ Science
/ Triple Negative Breast Neoplasms - genetics
/ Triple Negative Breast Neoplasms - metabolism
