Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Warfel NA, Kraft AS. PIM kinase (and Akt) biology and signaling in tumors. Pharmacol Ther. 2015;151:41–49.

    CAS  Article  Google Scholar 

  2. 2.

    Narlik-Grassow M, Blanco-Aparicio C, Carnero A. The PIM family of serine/threonine kinases in cancer. Med Res Rev. 2014;34:136–59.

    CAS  Article  Google Scholar 

  3. 3.

    Hospital MA, Jacquel A, Mazed F, Saland E, Larrue C, Mondesir J, et al. RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia. Leukemia. 2018;32:597–605.

    CAS  Article  Google Scholar 

  4. 4.

    Wang Z, Zhang Y, Gu JJ, Davitt C, Reeves R, Magnuson NS. Pim-2 phosphorylation ofp21(Cip1/WAF1) enhances its stability and inhibits cell proliferation in HCT116 cells. Int J Biochem Cell Biol. 2010;42:1030–8.

    CAS  Article  Google Scholar 

  5. 5.

    Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008;68:5076–85.

    CAS  Article  Google Scholar 

  6. 6.

    Lu J, Zavorotinskaya T, Dai Y, Niu XH, Castillo J, Sim J, et al. Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation. Blood. 2013;122:1610–20.

    CAS  Article  Google Scholar 

  7. 7.

    Yu Z, Zhao X, Huang L, Zhang T, Yang F, Xie L, et al. Proviral insertion in murine lymphomas 2 (PIM2) oncogene phosphorylates pyruvate kinase M2 (PKM2) and promotes glycolysis in cancer cells. J Biol Chem. 2013;288:35406–16.

    CAS  Article  Google Scholar 

  8. 8.

    Yu Z, Huang L, Qiao P, Jiang A, Wang L, Yang T, et al. PKM2 Thr454 phosphorylation increases its nuclear translocation and promotes xenograft tumor growth in A549 human lung cancer cells. Biochem Biophys Res Commun. 2016;473:953–8.

    CAS  Article  Google Scholar 

  9. 9.

    Yang T, Ren C, Qiao P, Han X, Wang L, Lv S, et al. PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. Oncogene. 2018;37:5997–6009.

    CAS  Article  Google Scholar 

  10. 10.

    Nair JR, Caserta J, Belko K, Howell T, Fetterly G, Baldino C, et al. Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma. Leukemia. 2017;31:1715–26.

    CAS  Article  Google Scholar 

  11. 11.

    Zhao YQ, Yin YQ, Liu J, Wang GH, Huang J, Zhu LJ, et al. Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer. Acta Pharmacol Sin. 2016;37:1237–50.

    CAS  Article  Google Scholar 

  12. 12.

    Kreuz S, Holmes KB, Tooze RM, Lefevre PF. Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas. Mol Cancer. 2015;14:205.

    CAS  Article  Google Scholar 

  13. 13.

    Daenthanasanmak A, Wu Y, Iamsawat S, Nguyen HD, Bastian D, Zhang M, et al. PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity. J Clin Investig. 2018;128:2787–2801.

    Article  Google Scholar 

  14. 14.

    Yu Z, Zhao X, Ge Y, Zhang T, Huang L, Zhou X, et al. A regulatory feedback loop between HIF-1alpha and PIM2 in HepG2 cells. PLoS ONE. 2014;9:e88301.

    Article  Google Scholar 

  15. 15.

    Ren C, Yang T, Qiao P, Wang L, Han X, Lv S, et al. PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis. Mol Oncol. 2018;12:690–704.

    CAS  Article  Google Scholar 

  16. 16.

    Onstad MA, Schmandt RE, Lu KH. Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment. J Clin Oncol. 2016;34:4225–30.

    CAS  Article  Google Scholar 

  17. 17.

    Ye S, Wen H, Jiang Z, Wu X. The effect of visceral obesity on clinicopathological features in patients with endometrial cancer: a retrospective analysis of 200 Chinese patients. BMC Cancer. 2016;16:209.

    Article  Google Scholar 

  18. 18.

    Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19:121–35.

    CAS  Article  Google Scholar 

  19. 19.

    Jansen M, Ten Klooster JP, Offerhaus GJ, Clevers H. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Physiol Rev. 2009;89:777–98.

    CAS  Article  Google Scholar 

  20. 20.

    Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66:789–800.

    CAS  Article  Google Scholar 

  21. 21.

    Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD, et al. Inhibition of AMPK catabolic action by GSK3. Mol Cell. 2013;50:407–19.

    CAS  Article  Google Scholar 

  22. 22.

    Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metab. 2012;16:104–12.

    CAS  Article  Google Scholar 

  23. 23.

    Hawley SA, Ross FA, Gowans GJ, Tibarewal P, Leslie NR, Hardie DG. Phosphorylation by Akt within the ST loop of AMPK-alpha1 down-regulates its activation in tumour cells. Biochem J. 2014;459:275–87.

    CAS  Article  Google Scholar 

  24. 24.

    Beharry Z, Mahajan S, Zemskova M, Lin YW, Tholanikunnel BG, Xia Z, et al. The Pim protein kinases regulate energy metabolism and cell growth. Proc Natl Acad Sci USA. 2011;108:528–33.

    CAS  Article  Google Scholar 

  25. 25.

    Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996;271:27879–87.

    CAS  Article  Google Scholar 

  26. 26.

    Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 2018;27:299–313.

    CAS  Article  Google Scholar 

  27. 27.

    Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17:113–24.

    CAS  Article  Google Scholar 

  28. 28.

    Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 2016;26:190–201.

    CAS  Article  Google Scholar 

  29. 29.

    Shukla K, Sonowal H, Saxena A, Ramana KV, Srivastava SK. Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells. Cancer Lett. 2017;411:57–63.

    CAS  Article  Google Scholar 

  30. 30.

    Zhou X, Chen J, Chen L, Feng X, Liu Z, Hu, et al. Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts. Cancer Lett. 2017;411:1–11.

    CAS  Article  Google Scholar 

  31. 31.

    Hall DT, Griss T, Ma JF, Sanchez BJ, Sadek J, Tremblay AMK, et al. The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation-associated cachectic muscle wasting. EMBO Mol Med. 2018;10:pii: e8307.

  32. 32.

    Bungard D, Fuerth BJ, Zeng PY, Faubert B, Maas NL, Viollet B, et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science. 2010;329:1201–5.

    CAS  Article  Google Scholar 

  33. 33.

    Yuan J, Ng WH, Yap J, Chia B, Huang X, Wang M, et al. The AMPK inhibitor overcomes the paradoxical effect of RAF inhibitors through blocking phospho-Ser-621 in the C terminus of CRAF. J Biol Chem. 2018;293:14276–84.

    CAS  Article  Google Scholar 

  34. 34.

    Yu Z, Ge Y, Xie L, Zhang T, Huang L, Zhao X, et al. Using a yeast two-hybrid system to identify FTCD as a new regulator for HIF-1alpha in HepG2 cells. Cell Signal. 2014;26:1560–6.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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).

Author information

Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Zhenhai Yu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/s41388-019-0898-z

Download citation

Further reading

Search

Quick links