title: Down-regulation of RIP1 by 2-deoxy-D-glucose sensitizes breast cancer cells to TRAIL-induced apoptosis.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising anticancer agent as it specifically kills a wide variety of cancer cells. However, resistance of subpopulations of cancer cells to TRAIL-induced cell death remains a major obstacle for successful treatment of cancer using TRAIL-based therapy. In this report we show that the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) efficiently enhances TRAIL-induced apoptosis through downregulation of receptor-interacting protein kinase 1 (RIP1) in breast cancer cells. Although 2-DG alone did not kill breast cancer cells, it sensitized the cells to TRAIL-induced cell death. This could be efficiently inhibited by blockage of the caspase cascade, suggesting 2-DG augments TRAIL-mediated apoptotic signaling. Indeed, treatment with 2-DG resulted in upregulation of TRAIL receptor 2 (TRAIL-R2), downregulation of cIAP1 and XIAP, and reduction in RIP1. The latter appeared to play an important role in regulating sensitivity of breast cancer cells to TRAIL, in that knockdown of RIP1 recapitulated, at least in part, the effect of 2-DG on TRAIL-induced apoptosis. Taken together, these results indicate that 2-DG enhances TRAIL-induced apoptosis in breast cancer cells by multiple mechanisms including suppression of RIP1, and highlight the potential therapeutic benefit of combinations of 2-DG and TRAIL in the treatment of breast cancer.
authors.affiliation: Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, PR China.
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Huang
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Long Jian
authors.initials: LJ
authors.lastname: Pu
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.forename: Jin Cheng
authors.initials: JC
authors.lastname: Xu
authors.forename: Zhi Wen
authors.initials: ZW
authors.lastname: Jiang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D015536:Down-Regulation; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: C119724:AGFG1 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D003847:Deoxyglucose; D053148:Caspase 3; D053181:Caspase 8