Department of Nuclear Medicine and Molecular Imaging, Ajou University School of Medicine, Suwon, Republic of Korea.
Institute of Medical Science, Ajou University School of Medicine, Suwon, Republic of Korea.
Sci Rep. 2020 Mar 13;10(1):4713. doi: 10.1038/s41598-020-61661-4.
The effect of cell cycle synchronisation on glucose metabolism in cancer cells is not known. We assessed how cell cycle synchronisation by thiazolidinediones (TZDs) can affect glucose uptake by cancer cells and investigated the anti-cancer effect of combination therapy with TZDs and 2-deoxy-glucose (2-DG) in colon cancer cells and in mouse xenograft models. Troglitazone (58.1 ± 2.0 vs 48.6 ± 1.3%, p = 0.002) or pioglitazone (82.9 ± 1.9 vs 61.6 ± 3.4%, p < 0.001) induced cell cycle arrest in SW480 cells at G1 phase. Western blot analysis showed the degradation of cyclin D1 and CDK4, and an increase in the expression levels of p21 and p27 after TZDs treatment. Withdrawal of troglitazone treatment induced significant increase in cellular H-DG uptake (141.5% ± 12.9% of controls) and membrane GLUT1 expression levels (146.3% of controls) by 24 h; 1 mM 2-DG treatment alone decreased cell survival by 5.8% as compared with the controls.; however, combination therapy enhanced the anti-tumour effects to 34.6% or 20.3% as compared with control cells. In vivo, each combination treatment group showed significant anti-tumour effects unlike the 2-DG alone group. Cell cycle synchronisation using TZDs induced cellular glucose uptake, which significantly enhanced the therapeutic effect of 2-DG in colon cancer.
细胞周期同步化对癌细胞葡萄糖代谢的影响尚不清楚。我们评估了噻唑烷二酮（TZDs）如何影响癌细胞的葡萄糖摄取，并研究了 TZDs 和 2-脱氧葡萄糖（2-DG）联合治疗在结肠癌细胞和小鼠异种移植模型中的抗癌作用。曲格列酮（58.1±2.0%比 48.6±1.3%，p=0.002）或吡格列酮（82.9±1.9%比 61.6±3.4%，p<0.001）诱导 SW480 细胞在 G1 期发生细胞周期阻滞。Western blot 分析显示 TZDs 处理后细胞周期蛋白 D1 和 CDK4 的降解，以及 p21 和 p27 的表达水平增加。曲格列酮治疗停药 24 小时后，细胞内 H-DG 摄取显著增加（比对照组增加 141.5%±12.9%），细胞膜 GLUT1 表达水平增加（比对照组增加 146.3%）；1mM 2-DG 单独处理与对照组相比，细胞存活率降低 5.8%；然而，联合治疗使肿瘤抑制作用增强至 34.6%或 20.3%，与对照组相比。在体内，与单独使用 2-DG 组相比，每种联合治疗组均表现出显著的抗肿瘤作用。TZDs 诱导的细胞周期同步化增加了细胞葡萄糖摄取，显著增强了 2-DG 在结肠癌中的治疗效果。
