AKT2 phosphorylation of hexokinase 2 at T473 promotes tumorigenesis and metastasis in colon cancer cells via NF-κB, HIF1α, MMP2, and MMP9 upregulation.

It has been well-established that AKT2 plays an important role in the development and progression of colon cancer; however, its precise function remains unclear. In the present study, we found that AKT2 can interact with and phosphorylate hexokinase 2 (HK2), the rate-limiting enzyme in glycolysis. Moreover, threonine phosphorylation dramatically increases its catalytic activity and enhances glycolysis. Mechanistically, AKT2 phosphorylation of HK2 at T473 was found to increase hexokinase activity and lactic acid production. A mutation in the AKT2 phosphorylation site of HK2 substantially reduced the stimulating effects of AKT2 on glycolysis, cellular apoptosis, invasion, tumorigenesis, and metastasis. In addition, AKT2 regulated NF-κB, HIF1Α, MMP2, and MMP9 via the phosphorylation of HK2 at the T473 site. Taken together, AKT2 increases the invasion, tumorigenesis, and metastasis of colon cancer cells in vitro and promotes lung metastasis in nude mice in vivo through the phosphorylation of the T473 site of HK2 by upregulating NF-κB, HIF1α, MMP2, and MMP9. In conclusion, our findings highlight a novel mechanism for the AKT2-HK2-NF-κB/HIF1α/MMP2/MMP9 axis in the regulation of colon cancer progression. Moreover, our results suggest that both AKT2 and HK2 may be potential targets for the treatment of colon cancer.