Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, PR China.
Department of Medical Microbiology, Weifang Medical University, Weifang, Shandong Province, PR China.
Oncogene. 2019 Sep;38(38):6537-6549. doi: 10.1038/s41388-019-0898-z. Epub 2019 Jul 29.
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 AMPKα1 kinase activity in EC cells. Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth. In addition, PIM2 expression positively correlated with AMPKα1 Thr467 phosphorylation in EC tissues. Further, treatment with a combination of the PIM2 inhibitor SMI-4a and the AMPKα1 activator AICAR could effectively inhibit tumor growth. Thus, our findings provide insight into the role of PIM2 and AMPKα1 in EC and suggest that combination targeting of these proteins may represent a new strategy for EC treatment.
子宫内膜癌（EC）是最常见的妇科恶性肿瘤之一。然而，EC 发生和发展的分子机制尚不清楚。在这里，我们证明蛋白原病毒插入物在鼠类淋巴瘤 2（PIM2）对于维持体内和体外 EC 肿瘤发生是必需的，并且可以抑制 EC 细胞中的 AMPKα1 激酶活性。具体而言，我们发现 PIM2 与 AMPKα1 结合，并直接在 Thr467 上磷酸化它。PIM2 对 AMPKα1 的磷酸化导致 AMPKα1 激酶活性降低，进而促进有氧糖酵解和肿瘤生长。此外，EC 组织中 PIM2 的表达与 AMPKα1 Thr467 的磷酸化呈正相关。此外，用 PIM2 抑制剂 SMI-4a 和 AMPKα1 激活剂 AICAR 的联合治疗可以有效抑制肿瘤生长。因此，我们的研究结果为 PIM2 和 AMPKα1 在 EC 中的作用提供了新的见解，并表明针对这些蛋白的联合靶向可能代表 EC 治疗的一种新策略。
