Journal
ONCOGENE
Volume 37, Issue 45, Pages 5997-6009Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0386-x
Keywords
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Funding
- Innovation Fund of National Natural Science Foundation of China [81602440, 81602301, 81471048]
- Shandong Province College Science and Technology Plan Project [J16LL08, J17KA254]
- Projects of Medical and Health Technology Development Program in Shandong province [2016WS0688, 2017WS398]
- National Natural Science Foundation of Shangdong Province [ZR2014HM086]
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Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and enhanced glucose starvation-induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer.
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