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A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells

Author

Listed:
  • Chiara Ghezzi

    (University of California
    University of California)

  • Alicia Wong

    (University of California
    University of California)

  • Bao Ying Chen

    (University of California
    University of California)

  • Bernard Ribalet

    (University of California)

  • Robert Damoiseaux

    (University of California
    University of California
    University of California)

  • Peter M. Clark

    (University of California
    University of California
    University of California
    University of California)

Abstract

Elevated glucose consumption is fundamental to cancer, but selectively targeting this pathway is challenging. We develop a high-throughput assay for measuring glucose consumption and use it to screen non-small-cell lung cancer cell lines against bioactive small molecules. We identify Milciclib that blocks glucose consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Milciclib blocks glucose consumption by targeting cyclin-dependent kinase 7 (CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Polymerase II phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data indicate that our high-throughput assay can identify compounds that regulate glucose consumption and that CDK7 is a key regulator of glucose consumption in cells with an activated PI3K pathway.

Suggested Citation

  • Chiara Ghezzi & Alicia Wong & Bao Ying Chen & Bernard Ribalet & Robert Damoiseaux & Peter M. Clark, 2019. "A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13334-8
    DOI: 10.1038/s41467-019-13334-8
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    Cited by:

    1. Robert Düster & Kanchan Anand & Sophie C. Binder & Maximilian Schmitz & Karl Gatterdam & Robert P. Fisher & Matthias Geyer, 2024. "Structural basis of Cdk7 activation by dual T-loop phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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