Park Ga B, Chung Yoon H, Kim Daejin
aDepartment of Biochemistry, Kosin University College of Medicine bDepartment of Anatomy, Chung-Ang University College of Medicine, Seoul cDepartment of Anatomy, Inje University College of Medicine, Busan, Republic of Korea.
Anticancer Drugs. 2017 Apr;28(4):410-420. doi: 10.1097/CAD.0000000000000472.
Cancer cell resistance to chemotherapy is associated with a poor prognosis. The compound 2-deoxy-D-glucose (2-DG) enhances the effect of chemotherapy against cancer cells lines in vitro and in vivo. However, its effect on the epithelial to mesenchymal transition (EMT) in drug-resistant cancer cells has not been fully elucidated. In this study, we investigated whether treatment of 5-fluorouracil or oxaliplatin-resistant colorectal cancer (CRC) cells with 2-DG suppressed their migratory activity and enhanced their susceptibility to chemotherapy. Chemoresistant CRC cells stably expressed drug resistance-related proteins (MDR1, MRP1, MRP2, and MRP3) and showed mesenchymal characteristics and a migratory phenotype. 2-DG treatment attenuated glycolysis-related enzyme expression, invasion activity, and EMT-related cytokine secretion in drug-resistant CRC cells. In addition, 2-DG inhibited the activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17. Gene silencing of ADAM10 and ADAM17 with small interfering RNA downregulated mesenchymal properties, reduced EMT-associated cytokine secretion, and rendered chemoresistant cells susceptible to anticancer drug treatment. Collectively, these findings suggest that increased glycolytic metabolism in drug-resistant cells has an effect on both migratory activity and cell viability through the activation of ADAM10 and ADAM17.
癌细胞对化疗的耐药性与预后不良相关。化合物2-脱氧-D-葡萄糖（2-DG）在体外和体内均可增强化疗对癌细胞系的作用。然而，其对耐药癌细胞上皮-间质转化（EMT）的影响尚未完全阐明。在本研究中，我们调查了用2-DG处理5-氟尿嘧啶或奥沙利铂耐药的结直肠癌（CRC）细胞是否会抑制其迁移活性并增强其对化疗的敏感性。化疗耐药的CRC细胞稳定表达耐药相关蛋白（MDR1、MRP1、MRP2和MRP3），并表现出间质特征和迁移表型。2-DG处理减弱了耐药CRC细胞中糖酵解相关酶的表达、侵袭活性和EMT相关细胞因子的分泌。此外，2-DG抑制了去整合素和金属蛋白酶10（ADAM10）及ADAM17的激活。用小干扰RNA对ADAM10和ADAM17进行基因沉默可下调间质特性，减少EMT相关细胞因子分泌，并使耐药细胞对抗癌药物治疗敏感。总的来说，这些发现表明，耐药细胞中糖酵解代谢的增加通过激活ADAM10和ADAM17对迁移活性和细胞活力均有影响。
