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ATM inhibitor KU‐55933 induces apoptosis and inhibits motility by blocking GLUT1‐mediated glucose uptake in aggressive cancer cells with sustained activation of Akt
Author(s) -
Harris Benjamin R. E.,
Zhang Ye,
Tao Jianxin,
Shen Renhui,
Zhao Xiaoqian,
Cleary Margot P.,
Wang Tong,
Yang DaQing
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001415rr
Subject(s) - glut1 , motility , apoptosis , protein kinase b , blocking (statistics) , cancer research , chemistry , glucose transporter , pharmacology , microbiology and biotechnology , medicine , biology , biochemistry , insulin , statistics , mathematics
Enhanced glucose uptake is coupled with elevated aerobic glycolysis (the Warburg effect) in cancer cells and is closely correlated with increased tumor aggressiveness and poor prognosis. We previously discovered that ATM, a protein kinase deficient in Ataxia‐telangiectasia (A‐T) disease, is an insulin‐responsive protein that participates in insulin‐mediated glucose uptake in muscle cells by stimulating glucose transporter 4 (GLUT4) translocation. However, the role of ATM in glucose uptake and tumorigenesis of cancer cells is unclear. In the present study, we found that aggressive breast and prostate cancer cell lines with overactivated Akt activity exhibit enhanced glucose uptake and GLUT1 translocation upon insulin treatment, and KU‐55933, a specific inhibitor of ATM, inhibits insulin‐mediated glucose uptake by blocking translocation of GLUT1 to the cell surface. KU‐55933 also inhibits aerobic glycolysis and ATP production in these cells. Moreover, KU‐55933 induces apoptosis and inhibits motility of cancer cells by inhibiting glucose uptake. Our results showed that while high concentration of glucose and insulin promote the expression of a mesenchymal biomarker (vimentin) in these cancer cells, KU‐55933 strongly inhibits its expression as well as epithelial to mesenchymal transition. The roles of ATM in stimulating glucose uptake, glycolysis, motility, and proliferation of cancer cells were demonstrated by knocking‐down ATM in these cells. KU‐55933 treatment also inhibits tumor growth and metastasis in vivo in mouse mammary tumors through inhibition of GLUT1 translocation and vimentin expression. These results suggest that ATM acts as a promoter of tumorigenesis in cancer cells with overactivated Akt, and KU‐55933 induces apoptosis and inhibits motility by blocking GLUT1‐mediated glucose uptake and glycolysis in these cancer cells, which may lead to the use of KU‐55933 and its analogs as new preventive or therapeutic agents against cancer.