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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 Ca 2+ and requires the Ca 2+ /calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca 2+ -dependent activation of AMPK in two different LKB1-null cancer cell lines caused G 1 -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 G 1 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 anticancer effects of genotoxic-based therapies. Mol Cancer Res; 16(2); 345-57. ©2017 AACR .

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