2-Deoxy-D-glucose enhances TRAIL-induced apoptosis in human melanoma cells through XBP-1-mediated up-regulation of TRAIL-R2.
2-Deoxy-D-glucose enhances TRAIL-induced apoptosis in human melanoma cells through XBP-1-mediated up-regulation of TRAIL-R2.
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DOI：
10.1186/1476-4598-8-122
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发表时间：
2009-12-14
期刊：
影响因子：
37.3
通讯作者：
Zhang XD
中科院分区：
文献类型：
--
作者：
Liu H;Jiang CC;Lavis CJ;Croft A;Dong L;Tseng HY;Yang F;Tay KH;Hersey P;Zhang XD
过去的研究表明，黑色素瘤细胞对TRAIL诱导的凋亡的敏感性在很大程度上与细胞表面TRAIL死亡受体的表达水平相关。然而，新鲜的黑色素瘤分离株和黑色素瘤组织切片通常表达低水平的TRAIL死亡受体。因此，除非与增加TRAIL死亡受体的细胞表面表达的药剂一起给予，否则TRAIL在治疗黑素瘤中的临床潜力可能是有限的。2-脱氧-D-葡萄糖（2-DG）是一种合成的葡萄糖类似物，可抑制糖酵解和糖基化并阻断细胞生长。它已在临床评价其作为抗癌剂的潜在用途。在这项研究中，我们研究了2-DG和TRAIL是否相互作用，以增强其对黑色素瘤细胞的细胞毒性。2-DG没有杀死黑色素瘤细胞，但在培养的黑色素瘤细胞和新鲜的黑色素瘤分离物中增强TRAIL诱导的凋亡。这与半胱天冬酶级联和线粒体凋亡途径的活化增加有关，并且通过抑制TRAIL-R2以及在较小程度上抑制TRAIL-R1来阻断。用2-DG处理上调黑素瘤细胞表面上的TRAIL死亡受体，特别是TRAIL-R2。TRAIL-R2的上调是由于不依赖于转录因子p53和CHOP的转录增加。相反，2-DG激活的未折叠蛋白反应的IRE 1 α和ATF 6途径似乎参与其中。此外，XBP-1，这是已知的转录调控的ATF 6和功能激活的IRE 1 α，被发现在2-DG介导的转录上调TRAIL-R2在黑色素瘤细胞中发挥重要作用。这些结果表明，2-DG通过未折叠蛋白反应的ATF 6/IRE 1 α/XBP-1轴上调TRAIL-2，使人黑素瘤细胞对TRAIL诱导的凋亡敏感。他们认为，2-DG是一种有前途的药剂，以增加治疗反应的TRAIL在黑色素瘤。
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. 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 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. These 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.
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影响因子：
11.2
作者：
Jiang, Chen Chen;Chen, Li Hua;Hersey, Peter
通讯作者：
Hersey, Peter
影响因子：
8
作者：
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64.5
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2.9
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