AMP-activated protein kinase (AMPK), a heterotrimeric serine/threonine kinase and cellular metabolic sensor, has been found to regulate cell cycle checkpoints in cancer cells in response to energetic stress, to harmonize proliferation with energy availability. Despite AMPK's emergent association with the cell cycle, it still has not been fully delineated how AMPK is regulated by upstream signaling pathways during mitosis. We report, for the first time, direct CDK1 phosphorylation of both the catalytic α1 and α2 subunits, as well as the β1 regulatory subunit, of AMPK in mitosis. We found that AMPK-knockout U2OS osteosarcoma cells have reduced mitotic indexes and that CDK1 phosphorylation-null AMPK is unable to rescue the phenotype, demonstrating a role for CDK1 regulation of mitotic entry through AMPK. Our results also denote a vital role for AMPK in promoting proper chromosomal alignment, as loss of AMPK activity leads to misaligned chromosomes and concomitant metaphase delay. Importantly, AMPK expression and activity was found to be critical for paclitaxel chemosensitivity in breast cancer cells and positively correlated with relapse-free survival in systemically treated breast cancer patients.

中文翻译：

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细胞周期蛋白依赖性激酶1介导的AMPK磷酸化调节染色体排列和有丝分裂进程。

AMP激活的蛋白激酶（AMPK）是一种异三聚体丝氨酸/苏氨酸激酶和细胞代谢传感器，已被发现可以调节癌细胞的细胞周期检查点，以应对精力充沛的压力，从而使增殖与能量可利用性相协调。尽管AMPK与细胞周期发生了关联，但仍没有完全描述有丝分裂期间上游信号通路如何调节AMPK。我们首次报道了有丝分裂中AMPK的催化α1和α2亚基以及β1调节亚基的直接CDK1磷酸化。我们发现，敲除AMPK的U2OS骨肉瘤细胞具有降低的有丝分裂指数，而CDK1磷酸化无效的AMPK无法挽救该表型，证明了CDK1调控通过AMPK进入有丝分裂的作用。我们的结果也表明AMPK在促进正确的染色体排列中起着至关重要的作用，因为AMPK活性的丧失会导致染色体排列错误和伴随的中期延迟。重要的是，发现AMPK的表达和活性对于乳腺癌细胞中紫杉醇的化学敏感性至关重要，并且与全身治疗的乳腺癌患者的无复发生存率呈正相关。