Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland, United Kingdom.
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland, United Kingdom.
Mol Cancer Res. 2018 Feb;16(2):345-357. doi: 10.1158/1541-7786.MCR-17-0323. Epub 2017 Nov 13.
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 and requires the Ca/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G-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 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. 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. .
许多致瘤性癌症治疗方法会激活 AMP 激活的蛋白激酶（AMPK），但 AMPK 对 DNA 损伤的激活机制及其下游后果尚不清楚。在这项研究中，依托泊苷激活 AMPK 的α1 同工型而非α2 同工型，主要在核内。AMPK 的激活不依赖于共济失调毛细血管扩张突变（ATM），一种 DNA 损伤激活的激酶，也是 AMPK 的主要上游激酶 LKB1，但与核内 Ca 增加相关，需要 Ca/钙调蛋白依赖性激酶，CaMKK2。有趣的是，两种不同的 LKB1 缺失型癌细胞系中，Ca 依赖性 AMPK 激活导致 G 期细胞周期停滞，并增强依托泊苷处理后的细胞活力/存活，这两种作用均被 AMPK-α1 和 α2 的敲除所消除。CDK4/6 抑制剂 palbociclib 也导致 G361 细胞中的 G 期停滞，但不导致 HeLa 细胞中的 G 期停滞，与这一结果一致的是，palbociclib 仅在 G361 细胞中增强依托泊苷处理后的细胞存活。这些结果表明，AMPK 激活通过限制细胞进入对遗传毒性更敏感的 S 期来保护细胞免受依托泊苷的侵害。这些结果表明，AMPK-α1 同工型通过保护细胞免受遗传毒性应激来促进肿瘤发生，这可能解释了在一些人类癌症中编码 AMPK-α1（而非 -α2）的基因被扩增的发现。此外，α1 选择性抑制剂可能增强基于遗传毒性的治疗方法的抗癌作用。
