Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2þ/CaMKK2 Signaling to Enhance Tumor Cell Survival

Vara-Ciruelos, Diana; Dandapani, Madhumita; Gray, Alexander; Egbani, Ejaife O.; Evans, A. Mark; Hardie, D. Grahame

Abstract

2017 American Association for Cancer Research. 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 a1 but not the a2 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 Ca2þ and requires the Ca2þ/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2þ-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-a1 and a2. 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 a1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-a1 (but not -a2) is amplified in some human cancers. Furthermore, a1-selective inhibitors might enhance the anticancer effects of genotoxic-based therapies.

Citation

Vara-Ciruelos, D., Dandapani, M., Gray, A., Egbani, E. O., Evans, A. M., & Hardie, D. G. (2018). Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2þ/CaMKK2 Signaling to Enhance Tumor Cell Survival. Molecular Cancer Research, 16(2), 345-357. https://doi.org/10.1158/1541-7786.mcr-17-0323

• Journal Article Type: Article
• Acceptance Date: Nov 1, 2017
• Online Publication Date: Nov 13, 2017
• Publication Date: 2018-02
• Deposit Date: Nov 15, 2019
• Journal: Molecular Cancer Research
• Print ISSN: 1541-7786
• Electronic ISSN: 1557-3125
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 2
• Pages: 345-357
• DOI: https://doi.org/10.1158/1541-7786.mcr-17-0323
• Public URL: https://nottingham-repository.worktribe.com/output/2142897