2. Academic Validation
  3. CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation

CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation

  • Neoplasia. 2019 Jul;21(7):713-720. doi: 10.1016/j.neo.2019.05.001.
Harri M Itkonen 1,  Ninu Poulose 2,  Suzanne Walker 3,  Ian G Mills 4
Affiliations

Affiliations

  • 1 Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, 0349, Norway; Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA. Electronic address: h.m.itkonen@gmail.com.
  • 2 PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, BT7 1NN, UK. Electronic address: ninurosa@gmail.com.
  • 3 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA. Electronic address: suzanne_walker@hms.harvard.edu.
  • 4 Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, 0349, Norway; PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, BT7 1NN, UK; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. Electronic address: ian.mills@linacre.ox.ac.uk.
PMID: 31151054 DOI: 10.1016/j.neo.2019.05.001
Abstract

Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymerase II, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate Cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate Cancer cells. This is manifested by a drastic down-regulation of mitochondrial Oxidative Phosphorylation, ATP depletion and induction of a rapid and sustained phosphorylation of AMP-activated protein kinase (AMPK), the key sensor of cellular energy homeostasis. We used metabolomics to demonstrate that inhibition of CDK9 leads to accumulation of acyl-carnitines, metabolic intermediates in fatty acid oxidation (FAO). Acyl-carnitines are produced by carnitine palmitoyltransferase Enzymes 1 and 2 (CPT), and we used both genetic and pharmacological tools to show that inhibition of CPT-activity is synthetically lethal with CDK9 inhibition. To our knowledge this is the first report to show that CDK9 inhibition dramatically alters Cancer cell metabolism.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12214A
    99.60%, CDK9 Inhibitor