Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University.
Center for Infectious Disease Education and Research (CiDER), Osaka University.
Cell Struct Funct. 2022 Dec 15;47(2):75-87. doi: 10.1247/csf.22034. Epub 2022 Nov 5.
Phosphatase of regenerating liver (PRL) is frequently overexpressed in various malignant cancers and is known to be a driver of malignancy. Here, we demonstrated that PRL overexpression causes mitotic errors that accompany spindle misorientation and aneuploidy, which are intimately associated with cancer progression. Mechanistic analyses of this phenomenon revealed dysregulation of the energy sensor kinase, AMP-activated protein kinase (AMPK), in PRL-induced mitotic errors. Specifically, immunofluorescence analysis showed that levels of phosphorylated AMPK (P-AMPK), an activated form of AMPK, at the kinetochore were reduced by PRL expression. Moreover, artificial activation of AMPK using chemical activators, such as A769662 and AICAR, in PRL-expressing cells restored P-AMPK signals at the kinetochore and normalized spindle orientation. Collectively, these results indicate the crucial importance of the activation of kinetochore-localized AMPK in the normal progression of mitosis, which is specifically perturbed by PRL overexpression.Key words: cancer, AMPK, PRL, kinetochore, mitotic errors.
肝再生磷酸酶（PRL）在各种恶性肿瘤中经常过表达，已知是恶性肿瘤的驱动因素。在这里，我们证明了 PRL 的过表达会导致伴随纺锤体取向错误和非整倍体的有丝分裂错误，这与癌症的进展密切相关。对这种现象的机制分析表明，PRL 诱导的有丝分裂错误中能量传感器激酶 AMP 激活蛋白激酶（AMPK）的失调。具体来说，免疫荧光分析表明，PRL 表达降低了着丝粒处磷酸化 AMPK（P-AMPK）的水平，即 AMPK 的激活形式。此外，在 PRL 表达细胞中使用化学激活剂（如 A769662 和 AICAR）人工激活 AMPK，可恢复着丝粒处的 P-AMPK 信号，并使纺锤体取向正常化。综上所述，这些结果表明着丝粒定位的 AMPK 的激活对于有丝分裂的正常进展至关重要，而 PRL 的过表达则特异性地破坏了这一过程。
癌症、AMPK、PRL、着丝粒、有丝分裂错误。
