2-Deoxy-D-glucose enhances TRAIL-induced apoptosis in human melanoma cells through XBP-1-mediated up-regulation of TRAIL-R2 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-12-14

AUTHORS

Hao Liu, Chen Chen Jiang, Christopher J Lavis, Amanda Croft, Li Dong, Hsin-Yi Tseng, Fan Yang, Kwang Hong Tay, Peter Hersey, Xu Dong Zhang

ABSTRACT

BackgroundPast 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.Results2-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 IRE1α 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 IRE1α, was found to play an important role in 2-DG-mediated transcriptional up-regulation of TRAIL-R2 in melanoma cells.ConclusionThese results indicate that 2-DG sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-2 via the ATF6/IRE1α/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. More... »

PAGES

122

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1476-4598-8-122

DOI

http://dx.doi.org/10.1186/1476-4598-8-122

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1037487578

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20003459


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51 anticancer agents
52 apoptosis
53 apoptotic pathway
54 axis
55 block cell growth
56 cascade
57 caspase cascade
58 cell growth
59 cell surface
60 cell surface expression
61 cells
62 clinical evaluation
63 clinical potential
64 cultured melanoma cells
65 cytotoxicity
66 death receptors
67 evaluation
68 expression
69 expression levels
70 extent
71 factors
72 fresh melanoma isolates
73 glucose analog
74 glycolysis
75 glycosylation
76 growth
77 human melanoma cells
78 important role
79 inhibition
80 isolates
81 lesser extent
82 levels
83 low levels
84 melanoma
85 melanoma cell surface
86 melanoma cells
87 melanoma tissue sections
88 mitochondrial apoptotic pathway
89 p53
90 pathway
91 potential
92 potential use
93 promising agent
94 protein response
95 receptors
96 regulation
97 response
98 results
99 role
100 sections
101 sensitivity
102 study
103 surface
104 surface expression
105 synthetic glucose analog
106 therapeutic response
107 tissue sections
108 trails
109 transcription
110 transcription factors
111 treatment
112 treatment of melanoma
113 unfolded protein response
114 use
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