The Hormel Institute, University of Minnesota, Austin, MN, USA.
Wuxi People's Hospital, Wuxi, People's Republic of China.
FASEB J. 2021 Apr;35(4):e21264. doi: 10.1096/fj.202001415RR.
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.
增强的葡萄糖摄取与癌症细胞中的有氧糖酵解（Warburg 效应）相关，与肿瘤侵袭性和不良预后密切相关。我们之前发现，ATM 是共济失调毛细血管扩张症（A-T）疾病中缺乏的蛋白激酶，是一种胰岛素反应蛋白，通过刺激葡萄糖转运蛋白 4（GLUT4）易位参与肌肉细胞中胰岛素介导的葡萄糖摄取。然而，ATM 在癌细胞葡萄糖摄取和肿瘤发生中的作用尚不清楚。在本研究中，我们发现 Akt 活性过度激活的侵袭性乳腺癌和前列腺癌细胞系在胰岛素处理后表现出增强的葡萄糖摄取和 GLUT1 易位，而 ATM 的特异性抑制剂 KU-55933 通过阻止 GLUT1 向细胞表面易位来抑制胰岛素介导的葡萄糖摄取。KU-55933 还抑制这些细胞中的有氧糖酵解和 ATP 产生。此外，KU-55933 通过抑制葡萄糖摄取诱导癌细胞凋亡和抑制其运动性。我们的结果表明，虽然高浓度的葡萄糖和胰岛素促进这些癌细胞中间充质生物标志物（波形蛋白）的表达，但 KU-55933 强烈抑制其表达以及上皮-间质转化。通过在这些细胞中敲低 ATM 证实了 ATM 在刺激葡萄糖摄取、糖酵解、运动性和增殖中的作用。KU-55933 处理还通过抑制 GLUT1 易位和波形蛋白表达抑制体内小鼠乳腺肿瘤的生长和转移。这些结果表明，ATM 在 Akt 过度激活的癌细胞中充当肿瘤发生的促进剂，而 KU-55933 通过阻断 GLUT1 介导的葡萄糖摄取和糖酵解诱导凋亡并抑制运动性，这可能导致使用 KU-55933 及其类似物作为新的预防或治疗癌症的药物。
