- Title
- Involvement of endoplasmic reticulum stress in docetaxel-induced JNK-dependent apoptosis of human melanoma
- Creator
- Mhaidat, Nizar M.; Thorne, Rick; Zhang, Xu Dong; Hersey, Peter
- Relation
- Apoptosis Vol. 13, Issue 12, p. 1505-1512
- Publisher Link
- http://dx.doi.org/10.1007/s10495-008-0276-8
- Publisher
- Springer
- Resource Type
- journal article
- Date
- 2008
- 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.
- Subject
- melanoma; docetaxel; ER stress; UPR; JNK; apoptosis
- Identifier
- uon:5394
- Identifier
- http://hdl.handle.net/1959.13/43273
- Identifier
- ISSN:1360-8185
- Reviewed
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