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

Harri M Itkonen, Ninu Poulose, Suzanne Walker, Ian G Mills

Research output: Contribution to journalArticle

57 Downloads (Pure)

Abstract

Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymeraseII, 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.

Original languageEnglish
Pages (from-to)713-720
Number of pages8
JournalNeoplasia
Volume21
Issue number7
Early online date28 May 2019
DOIs
Publication statusPublished - 01 Jul 2019

Fingerprint

Cyclin-Dependent Kinase 9
Prostatic Neoplasms
Fatty Acids
Carnitine
Carnitine O-Palmitoyltransferase
Physiological Stress
AMP-Activated Protein Kinases
Metabolomics
Oxidative Phosphorylation
Neoplasms
Homeostasis
Cell Death
Down-Regulation
Adenosine Triphosphate
Phosphorylation
Pharmacology
RNA
Enzymes

Bibliographical note

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Cite this

Itkonen, Harri M ; Poulose, Ninu ; Walker, Suzanne ; Mills, Ian G. / CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation. In: Neoplasia . 2019 ; Vol. 21, No. 7. pp. 713-720.
@article{dc7c7f9df36147758b773b06e178f111,
title = "CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation",
abstract = "Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymeraseII, 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.",
author = "Itkonen, {Harri M} and Ninu Poulose and Suzanne Walker and Mills, {Ian G}",
note = "Copyright {\circledC} 2019 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/j.neo.2019.05.001",
language = "English",
volume = "21",
pages = "713--720",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "7",

}

CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation. / Itkonen, Harri M; Poulose, Ninu; Walker, Suzanne; Mills, Ian G.

In: Neoplasia , Vol. 21, No. 7, 01.07.2019, p. 713-720.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation

AU - Itkonen, Harri M

AU - Poulose, Ninu

AU - Walker, Suzanne

AU - Mills, Ian G

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymeraseII, 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.

AB - Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymeraseII, 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.

U2 - 10.1016/j.neo.2019.05.001

DO - 10.1016/j.neo.2019.05.001

M3 - Article

C2 - 31151054

VL - 21

SP - 713

EP - 720

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 7

ER -