Negative regulation of AMPKα1 by PIM2 promotes aerobic glycolysis and tumorigenesis in endometrial cancer
Negative regulation of AMPKα1 by PIM2 promotes aerobic glycolysis and tumorigenesis in endometrial cancer
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PIM2 对 AMPKα1 的负调节促进子宫内膜癌的有氧糖酵解和肿瘤发生。
DOI：
10.1038/s41388-019-0898-z
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发表时间：
2019-09-19
期刊：
影响因子：
8
通讯作者：
Yu, Zhenhai
中科院分区：
文献类型：
--
作者：
Han, Xue;Ren, Chune;Yu, Zhenhai
子宫内膜癌是妇科最常见的恶性肿瘤之一。然而，EC发生和发展的分子机制仍不清楚。在这里，我们证明，蛋白质前病毒插入小鼠淋巴瘤2（PIM 2）是必要的，维持EC肿瘤在体内和体外，并能抑制AMPK α 1激酶活性EC细胞。具体地说，我们发现PIM 2结合AMPK α 1，并直接磷酸化它的Thr 467。AMPK α 1被PIM 2磷酸化导致AMPK α 1激酶活性降低，这反过来又促进有氧糖酵解和肿瘤生长。此外，在EC组织中，PIM 2表达与AMPK α 1 Thr 467磷酸化正相关。此外，用PIM 2抑制剂SMI-4a和AMPK α 1激活剂AICAR的组合治疗可以有效地抑制肿瘤生长。因此，我们的研究结果提供了深入了解PIM 2和AMPK α 1在EC中的作用，并表明这些蛋白质的组合靶向可能代表EC治疗的新策略。
Endometrial cancer (EC) is one of the most common gynecologic malignancies. However, the molecular mechanisms underlying the development and progression of EC remain unclear. Here, we demonstrated that the protein proviral insertion in murine lymphomas 2 (PIM2) was necessary for maintaining EC tumorigenesis in vivo and in vitro, and could inhibit AMPK alpha 1 kinase activity in EC cells. Specifically, we found that PIM2 bound to AMPK alpha 1, and directly phosphorylated it on Thr467. Phosphorylation of AMPK alpha 1 by PIM2 led to decreasing AMPK alpha 1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth. In addition, PIM2 expression positively correlated with AMPK alpha 1 Thr467 phosphorylation in EC tissues. Further, treatment with a combination of the PIM2 inhibitor SMI-4a and the AMPK alpha 1 activator AICAR could effectively inhibit tumor growth. Thus, our findings provide insight into the role of PIM2 and AMPK alpha 1 in EC and suggest that combination targeting of these proteins may represent a new strategy for EC treatment.