title: Glycolysis inhibition by 2-deoxy-D-glucose reverts the metastatic phenotype in vitro and in vivo.
abstract: Metastasis is the primary cause of death from many tumors, and novel anti-metastatic therapies are necessary. Recently, we showed that metastatic tumors down-regulate key oxidative phosphorylation (OXPHOS) genes in favor of glycolysis, a further enhancement of the Warburg effect. Therefore, we sought to determine if restriction of glycolysis using 2-deoxy-D-glucose (2DG) would lead to increased utilization of OXPHOS and inhibition of the metastatic phenotype. Noncytotoxic concentrations of 2DG dose-dependently inhibited in vitro migration and invasion in the highly metastatic DLM8-luc-M1 osteosarcoma (OS) cell line, as well as other metastatic human, canine, and murine cancer cells of different histotypes. This was associated with cytoskeletal rearrangement and inhibition of cathepsin L expression. A dose-dependent shift toward OXPHOS was confirmed by demonstrating increased oxygen utilization and decreased lactate production in 2DG treated cells. Finally, 2DG treatment significantly delayed metastasis and prolonged survival in an orthotopic postsurgical OS model. In conclusion, this work suggests that forcing cells away from glycolysis may inhibit key components of the metastatic phenotype, providing a novel avenue for metastasis prevention.
authors.affiliation: Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523-1620, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Sottnik
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lori
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Rose
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Thamm
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D056668:Cathepsin L / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005455:Fluorescent Antibody Technique; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010641:Phenotype; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000963:Antimetabolites; D003847:Deoxyglucose; D056668:Cathepsin L