Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration
Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration
复制标题
Aurora-A 介导的 LKB1 磷酸化损害 LKB1/AMPK 信号轴，促进 NSCLC 生长和迁移
DOI：
10.1038/onc.2017.354
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发表时间：
2018-01-25
期刊：
影响因子：
8
通讯作者：
Guo, J.
中科院分区：
文献类型：
--
作者：
Zheng, X.;Chi, J.;Guo, J.
LKB 1的缺失或功能丧失突变经常发生在非小细胞肺癌（NSCLC）中，是NSCLC发生和进展的主要原因。然而，控制LKB 1激活的上游信号通路在很大程度上是未知的。在这里，我们报告说，LKB 1经历极光激酶A（AURKA）介导的磷酸化，这在很大程度上损害了LKB 1/AMPK信号轴，从而导致非小细胞肺癌细胞增殖，侵袭和迁移的高度。在机制上，AURKA介导的LKB 1磷酸化损害LKB 1与其下游靶标AMPKα的相互作用和磷酸化，AMPK α在控制癌细胞能量代谢稳态和肿瘤发生中起关键作用。临床上，AURKA在NSCLC患者中表现出高水平，并与肺腺癌患者的不良结局相关。在病理学上，AURKA诱导的LKB 1/AMPK信号通路损伤的放大或激活有助于NSCLC的发生和进展，突出了AURKA作为对抗过度活跃的AURKA驱动的NSCLC的潜在治疗靶点。
Deletion or loss-of-function mutation of LKB1, frequently occurring in non-small cell lung cancers (NSCLCs), is a predominant caution of NSCLC initiation and progression. However, the upstream signaling pathways governing LKB1 activation are largely unknown. Here, we report that LKB1 undergoes Aurora kinase A (AURKA)-mediated phosphorylation, which largely compromises the LKB1/AMPK signaling axis, in turn leading to the elevation of NSCLC cell proliferation, invasion and migration. Mechanically, AURKA-mediated phosphorylation of LKB1 impairs LKB1 interaction with and phosphorylation of its downstream target AMPKα, which has critical roles in governing cancer cell energy metabolic homeostasis and tumorigenesis. Clinically, AURKA displays high levels in NSCLC patients, and correlates with poor outcome of patients with lung adenocarcinoma. Pathologically, the amplification or activation of AURKA-induced impairment of the LKB1/AMPK signaling pathway contributes to NSCLC initiation and progression, highlighting AURKA as a potential therapeutic target for combatting hyperactive AURKA-driven NSCLCs.