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

Hang Li; Shaohong Lu; Yu Chen; Longzhi Zheng; Liangyuan Chen; Haojie Ding; Jianzu Ding; Di Lou; Fangfang Liu; Bin Zheng

doi:10.1016/j.cellsig.2019.03.011

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

Cell Signal. 2019 Jun:58:99-110. doi: 10.1016/j.cellsig.2019.03.011. Epub 2019 Mar 12.

Authors

Hang Li¹, Shaohong Lu², Yu Chen¹, Longzhi Zheng¹, Liangyuan Chen³, Haojie Ding², Jianzu Ding², Di Lou², Fangfang Liu¹, Bin Zheng⁴

Affiliations

¹ Department of central laboratory, Affiliated Hospital of Putian University, Putian 351100, Fujian, PR China.
² Zhejiang Academy of Medical Sciences, Hangzhou 310013, Zhejiang, PR China.
³ Department of Clinical Laboratory, Fujian Provincial Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou 350025, Fujian, PR China.
⁴ Zhejiang Academy of Medical Sciences, Hangzhou 310013, Zhejiang, PR China. Electronic address: zhengb@zjams.com.cn.

PMID: 30877036
DOI: 10.1016/j.cellsig.2019.03.011

Abstract

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.

Keywords: AKT2; Colon cancer; HK2; Metastasis; Phosphorylation; Tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / metabolism
Carcinogenesis / pathology
Colonic Neoplasms / metabolism*
Colonic Neoplasms / pathology
Glycolysis
HCT116 Cells
HT29 Cells
Hexokinase / analysis
Hexokinase / metabolism*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / analysis
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Matrix Metalloproteinase 2 / analysis
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinase 9 / analysis
Matrix Metalloproteinase 9 / metabolism*
Mice, Inbred BALB C
Mice, Nude
NF-kappa B / analysis
NF-kappa B / metabolism*
Phosphorylation
Proto-Oncogene Proteins c-akt / analysis
Proto-Oncogene Proteins c-akt / metabolism*
Up-Regulation

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
NF-kappa B
HK2 protein, human
Hexokinase
AKT2 protein, human
Proto-Oncogene Proteins c-akt
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9