title: 2-Deoxy-D-glucose suppresses the migration and reverses the drug resistance of colon cancer cells through ADAM expression regulation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ga B
authors.initials: GB
authors.lastname: Park
authors.forename: Yoon H
authors.initials: YH
authors.lastname: Chung
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D000072197:ADAM10 Protein / Q000096:biosynthesis*; D000072198:ADAM17 Protein / Q000096:biosynthesis*; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D003847:Deoxyglucose / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006019:Glycolysis; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*
chemical_list: D008565:Membrane Proteins; D003847:Deoxyglucose; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human