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Updated: Jan 24, 2026

Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death
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CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation

Harri M Itkonen1, Ninu Poulose2, Suzanne Walker3

  • 1Centre 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.

Neoplasia (New York, N.Y.)
|June 1, 2019
PubMed

Insights

Inhibiting cyclin-dependent kinase 9 (CDK9) causes metabolic stress in prostate cancer cells. Blocking carnitine palmitoyltransferase (CPT) activity together with CDK9 inhibition is synthetically lethal, offering a potential cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • Cyclin-dependent kinase 9 (CDK9) regulates RNA-polymerase II and is a drug target for cancers with transcriptional deregulation.
  • Prostate cancer is driven by complex molecular pathways, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify synthetic lethal interactions by profiling prostate cancer cell responses to CDK9 inhibition.
  • To investigate the metabolic consequences of CDK9 inhibition in prostate cancer cells.

Main Methods:

  • Multi-omics profiling of prostate cancer cells.
  • Live-cell imaging, mitochondrial flux, viability, and cell death assays.
  • Metabolomics, genetic, and pharmacological inhibition of carnitine palmitoyltransferase (CPT).

Main Results:

  • CDK9 inhibition induces acute metabolic stress, down-regulating mitochondrial oxidative phosphorylation and depleting ATP.
  • AMP-activated protein kinase (AMPK) phosphorylation is rapidly induced, signaling energy depletion.
  • Inhibition of CDK9 leads to acyl-carnitine accumulation, indicating altered fatty acid oxidation (FAO).
  • CPT inhibition is synthetically lethal with CDK9 inhibition in prostate cancer cells.

Conclusions:

  • CDK9 inhibition profoundly alters cancer cell metabolism, inducing significant metabolic stress.
  • Targeting carnitine palmitoyltransferase (CPT) in combination with CDK9 inhibition presents a novel synthetic lethal strategy for prostate cancer treatment.

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