Involvement of endoplasmic reticulum stress in Docetaxel-induced JNK-dependent apoptosis of human melanoma.
Our previous studies revealed that Docetaxel-induced 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 Docetaxel-induced activation of proteins involved in ER stress signalling namely GRP78, ATF6, IRE1alpha, and PERK/eIF2alpha. Knockdown of IRE1alpha by siRNA markedly inhibited Docetaxel-induced JNK activation and downstream targets of JNK indicating that activation of IRE1alpha 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 IRE1alpha-TRAF2-ASK1 complex. ER stress mediated activation of the JNK pathway is downstream of activation of PKCdelta in that downregulation of PKCdelta expression using specific PKCdelta siRNA significantly inhibited Docetaxel-induced activation of IRE1alpha and the JNK pathway. These findings provide new insights to understand the mode of action of taxanes in treatment of human melanoma.
Mhaidat
Nizar M
NM
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan. nizarm@just.edu.jo
Thorne
Rick
R
Zhang
Xu Dong
XD
Hersey
Peter
P
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D047992:TNF Receptor-Associated Factor 2; D043823:Taxoids; D000077143:Docetaxel; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D004722:Endoribonucleases; D002118:Calcium