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.
Highlights
TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising candidate for cancer therapeutics because of its ability to preferentially induce apoptosis in malignant cells [1,2,3]
We have previously shown that sensitivity of cultured melanoma cells to TRAIL-induced apoptosis is in general correlated with the levels of the cell surface expression of TRAIL death receptors, in particular, TRAIL-R2 [9,10]
Deficiency in CCAAT/enhancer-binding protein-homologous protein (CHOP) did not appear to significantly impact on the increase in TRAIL-R2 induced by 2-DG at both the protein and mRNA levels (Figure 5D). These results indicate that neither p53 nor CHOP plays a role in 2-DG-mediated up-regulation of TRAIL-R2 in melanoma cells
Summary
TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising candidate for cancer therapeutics because of its ability to preferentially induce apoptosis in malignant cells [1,2,3]. We have previously shown that sensitivity of cultured melanoma cells to TRAIL-induced apoptosis is in general correlated with the levels of the cell surface expression of TRAIL death receptors, in particular, TRAIL-R2 [9,10]. Studies on melanoma tissue sections revealed that reduced TRAIL-R2 expression is associated with disease progression and a poor prognosis [14] Taken together, these studies indicate that melanoma may not respond to treatment with TRAIL unless given with agents that increase the cell surface expression of TRAIL death receptors, in particular, TRAIL-R2. 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. 2-Deoxy-D-glucose (2DG) 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. We have examined whether 2-DG and TRAIL interact to enhance their cytotoxicity towards melanoma cells
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