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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 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.

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The study was supported by research grants from Innovation fund of National Natural Science Foundation of China (Grant no. 81602440, 81602301, 81501275 and 81471048), Shandong Province College Science and Technology Plan Project (Grant no. J16LL08 and J17KA254), Projects of medical and health technology development program in Shandong province (Grant no. 2016WS0688 and 2017WS398).

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ZY designed research. XH, CR, TY, QP, and LW performed research. AJ, YM, YD, and ZL contributed new reagents/analytic tools. ZY and XH analyzed data. ZY wrote and revised the paper.

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Correspondence to Zhenhai Yu.

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Han, X., Ren, C., Yang, T. et al. Negative regulation of AMPKα1 by PIM2 promotes aerobic glycolysis and tumorigenesis in endometrial cancer. Oncogene 38, 6537–6549 (2019).

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