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Deciphering the role of CDK4 in regulating metabolism and cell fate of triple-negative breast cancer cells

ABSTRACT: The shift on energetic demands of proliferating cells during tumorigenesis requires an intense crosstalk between cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism of normal tissues. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduces cell proliferation of triple negative breast cancer (TNBC) cell line and allows in vivo tumor formation. Furthermore, pro-apoptotic stimuli fail to induce proper cell death in CDK4-silenced, depleted or long-term CDK4/6 inhibitors-treated TNBC cells, with dampened mitochondrial calcium uptake. In the second mass spectrometry-based experiment linked to this project, we used TMT technology to assay the proteome and phosphoproteome of WT and Cdk4 KO cells triple negative breast cancer cells (MDA-MB-231) subjected to mitophagic stress, i.e. a treatment with Oligomycin + Antimycin A.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Cancer Cell Line, Mammary Gland

DISEASE(S): Breast Cancer

SUBMITTER: Manfredo Quadroni

LAB HEAD: Lluis Fajas

PROVIDER: PXD046353 | Pride | 2024-11-26

REPOSITORIES: Pride

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			Action	DRS
	220613_Ziegler_TMT_14623-12-5_CV40-60.raw	Raw
	220613_Ziegler_TMT_14623-12-5_CV50-70.raw	Raw
	220613_Ziegler_TMT_14623-15_CV40-60.raw	Raw
	220613_Ziegler_TMT_14623-15_CV50-70.raw	Raw
	220613_Ziegler_TMT_14623-17-5_CV40-60.raw	Raw

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Deciphering the role of CDK4 in regulating metabolism and cell fate of triple-negative breast cancer cells

Project description:The shift on energetic demands of proliferating cells during tumorigenesis requires an intense crosstalk between cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism of normal tissues. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduces cell proliferation of triple negative breast cancer (TNBC) cell line and allows in vivo tumor formation. Furthermore, pro-apoptotic stimuli fail to induce proper cell death in CDK4-silenced, depleted or long-term CDK4/6 inhibitors-treated TNBC cells, with dampened mitochondrial calcium uptake. In the third mass spectrometry-based experiment linked to this project, we assayed the proteome and phosphoproteome of purified mitochondria-ER junctions in WT and Cdk4 KO triple negative breast cancer cells (MDA-MB-231).

2024-11-26 | PXD046327 | Pride

Deciphering the role of CDK4 in regulating metabolism and cell fate of triple-negative breast cancer cells

Project description:The shift on energetic demands of proliferating cells during tumorigenesis requires an intense crosstalk between cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism of normal tissues. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduces cell proliferation of triple negative breast cancer (TNBC) cell line and allows in vivo tumor formation. Furthermore, pro-apoptotic stimuli fail to induce proper cell death in CDK4-silenced, depleted or long-term CDK4/6 inhibitors-treated TNBC cells, with dampened mitochondrial calcium uptake. In the first mass spectrometry-based experiment linked to this project, we explored the proteome and phosphoproteome of WT vs CDK4 KO in triple negative breast cancer cells (MDA-MB-231).

2024-11-26 | PXD046326 | Pride

CDK4/6 inhibitors induce repication stress to cause long-term cell cycle withdrawal

Project description:CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are licenced to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a temporary cell cycle arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that chemotherapeutics that cause replication stress also induce sensitivity to CDK4/6 inhibition.

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BCL2L13 regulates sarcoplasmic reticulum-mitochondria calcium flux in skeletal muscle

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2023-11-06 | PXD041943 | Pride

CDK4 Inactivation Hinders Cell Death and Metabolism Remodeling Mitochondria-ER contacts in Triple-Negative Breast cancer cells

Project description:The shift in the energetic demands of proliferating cells during tumorigenesis requires extensive crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Here, using both genetic and pharmacological approaches, we sought to determine the metabolic role of CDK4 in triple-negative breast cancer (TNBC) cells. Unexpectedly, the deletion of CDK4 only modestly reduced TNBC cell proliferation and did not hinder tumor formation in vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells upon CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERC) formation, thereby promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. Such CDK4-mediated mitochondrial calcium signaling is required for the metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance by inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting of MERCs-associated metabolic shifts.

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NINJ1 induces plasma membrane rupture and DAMP release during ferroptosis

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Project description:CDK4/6 inhibitors (CDK4/6i) have significantly improved the prognosis for hormone-positive (HR+) breast cancer patients. However, the emergence of drug resistance severely limits their long-term efficacy, and CDK4/6i monotherapy remains largely ineffective against triple-negative breast cancer (TNBC). Here, we demonstrate that combining CDK4/6i with CDK7 inhibitors (CDK7i) offers a promising therapeutic strategy to overcome resistance in both HR+ breast cancer and TNBC. Kinetic analyses reveal that CDK7i primarily targets RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance by amplifying E2F activity following the degradation of the retinoblastoma protein. Consequently, the combination of CDK4/6i and CDK7i synergistically suppresses E2F activity and inhibits the growth of drug-resistant tumors. Furthermore, this combination stimulates immune response pathways and cytokine production in cancer cells, enhancing anti-tumor immunity. These findings provide critical insights into evolving CDK inhibition strategies and highlight the therapeutic application of CDK7i in breast cancer management.

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