Negative regulation of AMPKα1 by PIM2 promotes aerobic glycolysis and tumorigenesis in endometrial cancer

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.