title: 2-Deoxy-D-glucose enhances TRAIL-induced apoptosis in human melanoma cells through XBP-1-mediated up-regulation of TRAIL-R2.
abstract: BACKGROUND
  Past studies have shown that sensitivity of melanoma cells to TRAIL-induced apoptosis is largely correlated with the expression levels of TRAIL death receptors on the cell surface. However, fresh melanoma isolates and melanoma tissue sections express generally low levels of death receptors for TRAIL. The clinical potential of TRAIL in the treatment of melanoma may therefore be limited unless given with agents that increase the cell surface expression of TRAIL death receptors. 2-Deoxy-D-glucose (2-DG) is a synthetic glucose analogue that inhibits glycolysis and glycosylation and blocks cell growth. It has been in clinical evaluation for its potential use as an anticancer agent. In this study, we have examined whether 2-DG and TRAIL interact to enhance their cytotoxicity towards melanoma cells.
  
  
  RESULTS
  2-DG did not kill melanoma cells, but enhanced TRAIL-induced apoptosis in cultured melanoma cells and fresh melanoma isolates. This was associated with increased activation of the caspase cascade and mitochondrial apoptotic pathway, and was blocked by inhibition of TRAIL-R2, and to a lesser extent, inhibition of TRAIL-R1. Treatment with 2-DG up-regulated TRAIL death receptors, in particular, TRAIL-R2, on the melanoma cell surface. Up-regulation of TRAIL-R2 was due to increased transcription that was not dependent on the transcription factors, p53 and CHOP. Instead, the IRE1 alpha and ATF6 pathways of the unfolded protein response that were activated by 2-DG appeared to be involved. Moreover, XBP-1, which is known to be transcriptionally regulated by ATF6 and functionally activated by IRE1 alpha, was found to play an important role in 2-DG-mediated transcriptional up-regulation of TRAIL-R2 in melanoma cells.
  
  
  CONCLUSIONS
  These results indicate that 2-DG sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-2 via the ATF6/IRE1 alpha/XBP-1 axis of the unfolded protein response. They suggest that 2-DG is a promising agent to increase the therapeutic response to TRAIL in melanoma.
authors.affiliation: Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, NSW, Australia. liuhao6886@yahoo.com.cn
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lavis
authors.forename: Amanda
authors.initials: A
authors.lastname: Croft
authors.forename: Li
authors.initials: L
authors.lastname: Dong
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Tseng
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Kwang Hong
authors.initials: KH
authors.lastname: Tay
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D003847:Deoxyglucose / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000071701:Regulatory Factor X Transcription Factors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D003847:Deoxyglucose