Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival

Diana Vara Ciruelos, Madhumita Dandapani, Alexander Gray, Ejaife O. Agbani, A. Mark Evans, D. Grahame Hardie (Lead / Corresponding author)

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Abstract

Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2+-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell cycle arrest, and enhanced cell viability/survival after etoposide treatment, with both effects being abolished by knockout of AMPK-α1 and -α2. The CDK4/6 inhibitor palbociclib also caused G1-arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S-phase, where cells would be more vulnerable to genotoxic stress. Implications: These results reveal that the α1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-α1 (but not -α2) is amplified in some human cancers. Furthermore, α1-selective inhibitors might enhance the anti-cancer effects of genotoxic-based therapies.
Original languageEnglish
Pages (from-to)345-357
Number of pages13
JournalMolecular Cancer Research
Volume16
Issue number2
Early online date13 Nov 2017
DOIs
Publication statusPublished - Feb 2018

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AMP-Activated Protein Kinases
Cell Survival
Protein Isoforms
Etoposide
DNA Damage
Neoplasms
G1 Phase Cell Cycle Checkpoints
Ataxia Telangiectasia
Null Lymphocytes
Calcium-Calmodulin-Dependent Protein Kinases
G1 Phase
S Phase
HeLa Cells
Carcinogenesis
Phosphotransferases
Cell Line

Keywords

  • AMP-activated protein kinase
  • CaMKK2
  • DNA damage
  • Etoposide
  • Cell survival

Cite this

@article{9590265a58bc4028a8e32571cd488315,
title = "Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival",
abstract = "Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2+-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell cycle arrest, and enhanced cell viability/survival after etoposide treatment, with both effects being abolished by knockout of AMPK-α1 and -α2. The CDK4/6 inhibitor palbociclib also caused G1-arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S-phase, where cells would be more vulnerable to genotoxic stress. Implications: These results reveal that the α1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-α1 (but not -α2) is amplified in some human cancers. Furthermore, α1-selective inhibitors might enhance the anti-cancer effects of genotoxic-based therapies.",
keywords = "AMP-activated protein kinase, CaMKK2, DNA damage, Etoposide, Cell survival",
author = "{Vara Ciruelos}, Diana and Madhumita Dandapani and Alexander Gray and Agbani, {Ejaife O.} and Evans, {A. Mark} and Hardie, {D. Grahame}",
note = "DVC was supported by a Programme Grant (C37030/A15101) awarded to DGH by Cancer Research UK, MD by a Clinical PhD studentship from the Wellcome Trust, and AG by a Senior Investigator Award (097726) to DGH by the Wellcome Trust. DGH was also indirectly supported by the pharmaceutical companies supporting the Division of Signal Transduction Therapy at Dundee (Boehringer-Ingelheim, GlaxoSmithKline and Merck KgaA). OAE and AME were supported by a Programme Grant (081195) from the Wellcome Trust.",
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Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival. / Vara Ciruelos, Diana; Dandapani, Madhumita; Gray, Alexander; Agbani, Ejaife O. ; Evans, A. Mark ; Hardie, D. Grahame (Lead / Corresponding author).

In: Molecular Cancer Research, Vol. 16, No. 2, 02.2018, p. 345-357.

Research output: Contribution to journalArticle

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AU - Vara Ciruelos, Diana

AU - Dandapani, Madhumita

AU - Gray, Alexander

AU - Agbani, Ejaife O.

AU - Evans, A. Mark

AU - Hardie, D. Grahame

N1 - DVC was supported by a Programme Grant (C37030/A15101) awarded to DGH by Cancer Research UK, MD by a Clinical PhD studentship from the Wellcome Trust, and AG by a Senior Investigator Award (097726) to DGH by the Wellcome Trust. DGH was also indirectly supported by the pharmaceutical companies supporting the Division of Signal Transduction Therapy at Dundee (Boehringer-Ingelheim, GlaxoSmithKline and Merck KgaA). OAE and AME were supported by a Programme Grant (081195) from the Wellcome Trust.

PY - 2018/2

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N2 - Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2+-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell cycle arrest, and enhanced cell viability/survival after etoposide treatment, with both effects being abolished by knockout of AMPK-α1 and -α2. The CDK4/6 inhibitor palbociclib also caused G1-arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S-phase, where cells would be more vulnerable to genotoxic stress. Implications: These results reveal that the α1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-α1 (but not -α2) is amplified in some human cancers. Furthermore, α1-selective inhibitors might enhance the anti-cancer effects of genotoxic-based therapies.

AB - Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2+-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell cycle arrest, and enhanced cell viability/survival after etoposide treatment, with both effects being abolished by knockout of AMPK-α1 and -α2. The CDK4/6 inhibitor palbociclib also caused G1-arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S-phase, where cells would be more vulnerable to genotoxic stress. Implications: These results reveal that the α1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-α1 (but not -α2) is amplified in some human cancers. Furthermore, α1-selective inhibitors might enhance the anti-cancer effects of genotoxic-based therapies.

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