Carcinogenesis Advance Access originally published online on July 25, 2007
Carcinogenesis 2007 28(11):2328-2336; doi:10.1093/carcin/bgm173
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Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response
Immunology and Oncology Unit, David Maddison Clinical Sciences Building, Newcastle Misericordiae Hospital, Cnr. King & Watt Streets, Newcastle, New South Wales 2300, Australia
* To whom correspondence should be addressed. Tel: +61 2 49 236828; Fax: +61 2 49236184;Email: peter.hersey{at}newcastle.edu.au Correspondence may also be addressed to Dr Xu Dong Zhang. Tel: +61 2 49 236194; Fax: +61 2 49 236184Email: xu.zhang{at}newcastle.edu.au
We have previously reported that sensitivity of melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is largely correlated with the levels of expression of TRAIL death receptors, in particular, TRAIL-R2 on the cell surface. However, fresh melanoma isolates and melanoma tissue sections express, in general, low levels of death receptors for TRAIL. We show in this study that the endoplasmic reticulum stress inducer, thapsigargin (TG), selectively up-regulated TRAIL-R2 and enhanced TRAIL-induced apoptosis in melanoma cells. However, the TRAIL-R2 pathway did not appear to be involved in induction of apoptosis by TG alone. Up-regulation of TRAIL-R2 appeared to be cooperatively mediated by the inositol-requiring transmembrane kinase and endonuclease 1
(IRE1)- and activation of transcription factor (ATF)-6-signaling pathways of the unfolded protein response (UPR) and the transcription factor CCAAT/enhancer-binding protein-homologous protein (CHOP). The latter played a critical role in the initial phase of the increase in TRAIL-R2 as small interfering RNA (siRNA) knockdown of CHOP blocked up-regulation of TRAIL-R2 only at a relatively early stage (16 h) after exposure to TG. In contrast, IRE1 and ATF6 appeared to be crucial in maintaining the increased levels of TRAIL-R2 in that siRNA knockdown of IRE1 or ATF6 had no effect on the increase in TRAIL-R2 at the initial phase, but blocked TRAIL-R2 up-regulation at a relatively late stage (36 h). Our results indicate that modulation of the UPR may be useful in sensitizing melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2.
Abbreviations: ATF, activation of transcription factor; eIF2, eukaryotic initiation factor ; ER, endoplasmic reticulum; HUVEC, human umbilical vein endothelial cell; IRE1, inositol-requiring transmembrane kinase and endonuclease 1; mRNA, messenger RNA; PCR, polymerase chain reaction; PERK, protein kinase-like endoplasmic reticulum kinase; siRNA, small interfering RNA; TG, thapsigargin; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; XBP1, X-box-binding protein 1; CHOP, CCAAT/enhancer-binding protein-homologous protein; FADD, Fas-associated death domain
These authors contributed equally to this work. Received May 9, 2007; revised June 19, 2007; accepted July 17, 2007.
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