Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/43273

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Title
Involvement of endoplasmic reticulum stress in docetaxel-induced JNK-dependent apoptosis of human melanoma
Author/Creator
Mhaidat, Nizar M.;  Thorne, Rick;  Zhang, Xu Dong;  Hersey, Peter
Institution
The University of Newcastle. Faculty of Health, School of Biomedical Sciences and Pharmacy
Description
Our previous studies revealed that Docetaxelinduced apoptosis of melanoma cells is entirely dependent on activation of the JNK signalling pathway. Here, we show that Docetaxel-induced apoptosis is mediated by induction of ER stress. This was shown by Docetaxelinduced activation of proteins involved in ER stress signalling namely GRP78, ATF6, IRE1α, and PERK/eIF2α. Knockdown of IRE1α by siRNA markedly inhibited Docetaxel-induced JNK activation and downstream targets of JNK indicating that activation of IRE1α was upstream of activation of the JNK. Co-immunoprecipitation experiments showed that activation of JNK is due to activation of ASK1 through formation of an IRE1α-TRAF2-ASK1 complex. ER stress mediated activation of the JNK pathway is downstream of activation of PKCδ in that downregulation of PKCδ expression using specific PKCδ siRNA significantly inhibited Docetaxel-induced activation of IRE1α and the JNK pathway. These findings provide new insights to understand the mode of action of taxanes in treatment of human melanoma.
Relation
Apoptosis Vol. 13, Issue 12, p. 1505-1512
Publisher Link
http://dx.doi.org/10.1007/s10495-008-0276-8
Date
2008
Publisher
Springer
Keyword(s)
melanoma;  docetaxel;  ER stress;  UPR;  JNK;  apoptosis
Resource Type
journal article
Identifier
http://hdl.handle.net/1959.13/43273
Identifier
ISSN:1360-8185
Reviewed
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Subject
"Apoptosis"
 
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