Carcinogenesis Advance Access published online on July 25, 2007
Carcinogenesis, 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, Newcastle Misericordiae Hospital, NSW, Australia
Address for Correspondence to: Dr. Peter Hersey or Dr. Xu Dong Zhang, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, Newcastle, NSW 2300, Australia. Ph: 61 2 49 236828. Fax: 61 2 49236184., Email: Peter.Hersey{at}newcastle.edu.au or Xu.Zhang{at}newcastle.edu.au
We have previously reported that sensitivity of melanoma cells to 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 ER stress inducer, thapsigargin, 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 thapsigargin alone. Up-regulation of TRAIL-R2 appeared to be cooperatively mediated by the IRE1
and ATF6 signaling pathways of the unfolded protein response and the transcription factor CHOP. The latter played a critical role in the initial phase of the increase in TRAIL-R2 as siRNA knockdown of CHOP blocked up-regulation of TRAIL-R2 only at a relatively early stage (16 hours) after exposure to thapsigargin. 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 hours). Our results indicate that modulation of the unfolded protein response may be useful in sensitizing melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2.
Key Words: Melanoma • TRAIL • Apoptosis • Thapsigargin • the UPR
1 These authors contributed equally to this work.
Received May 9, 2007; revised June 19, 2007; accepted July 17, 2007.
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