Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents* / pharmacology
-
Antineoplastic Agents* / therapeutic use
-
Apoptosis / drug effects*
-
Calcium / metabolism
-
Cell Line, Tumor
-
Docetaxel
-
Endoplasmic Reticulum / drug effects
-
Endoplasmic Reticulum / metabolism*
-
Endoplasmic Reticulum Chaperone BiP
-
Endoribonucleases / genetics
-
Endoribonucleases / metabolism
-
Enzyme Activation
-
Humans
-
JNK Mitogen-Activated Protein Kinases / genetics
-
JNK Mitogen-Activated Protein Kinases / metabolism*
-
MAP Kinase Kinase Kinase 5 / genetics
-
MAP Kinase Kinase Kinase 5 / metabolism
-
Melanoma* / drug therapy
-
Melanoma* / metabolism
-
Protein Kinase C / metabolism
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism
-
Signal Transduction / physiology
-
TNF Receptor-Associated Factor 2 / genetics
-
TNF Receptor-Associated Factor 2 / metabolism
-
Taxoids* / pharmacology
-
Taxoids* / therapeutic use
Substances
-
Antineoplastic Agents
-
Endoplasmic Reticulum Chaperone BiP
-
HSPA5 protein, human
-
TNF Receptor-Associated Factor 2
-
Taxoids
-
Docetaxel
-
ERN1 protein, human
-
Protein Serine-Threonine Kinases
-
Protein Kinase C
-
JNK Mitogen-Activated Protein Kinases
-
MAP Kinase Kinase Kinase 5
-
MAP3K5 protein, human
-
Endoribonucleases
-
Calcium