Back to Search
Start Over
Docetaxel-induced apoptosis of human melanoma is mediated by activation of c-Jun NH2-terminal kinase and inhibited by the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 pathway.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2007 Feb 15; Vol. 13 (4), pp. 1308-14. - Publication Year :
- 2007
-
Abstract
- Purpose: Our studies have shown variable sensitivity of cultured melanoma cells to docetaxel. To better understand this response, we studied the role of signal transduction pathways in modulating docetaxel-induced melanoma killing.<br />Experimental Design: Involvement of c-Jun NH(2)-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt signaling was studied by evaluating their extent of activation in melanoma cells after treatment with docetaxel. The effect of their activation on docetaxel-induced apoptosis was assessed using biochemical inhibitors of the pathways and Western blot analysis of proteins involved.<br />Results: Docetaxel induced activation of both JNK and ERK1/2 but not p38 mitogen-activated protein kinase or Akt kinases. Apoptosis was dependent on activation of JNK and mediated through activation of caspase-2 and caspase-dependent changes in Bax and Bak. The levels of activated JNK in individual lines showed a close correlation with the levels of apoptosis. In contrast, activation of ERK1/2 by docetaxel inhibited apoptosis and the levels of activation in individual lines were inversely correlated to the degree of apoptosis. Studies on the Bcl-2 family proteins seemed to reflect changes induced by activation of JNK and ERK1/2 pathways. Docetaxel-induced JNK activation was required for Bcl-2 phosphorylation as well as caspase-2-dependent activation of Bax and Bak and subsequent mitochondrial release of apoptosis-inducing factor and cytochrome c. In contrast, activation of ERK1/2 resulted in degradation of BH3-only protein Bim and phosphorylation of Bad.<br />Conclusions: These studies provide further insights into sensitivity of melanoma cells to taxanes and provide a basis for the current rationale of combining taxanes with inhibitors of the Raf-ERK1/2 pathway.
- Subjects :
- Caspase 2 metabolism
Cell Line, Tumor
Docetaxel
Enzyme Activation
Genes, bcl-2
Humans
MAP Kinase Signaling System drug effects
Melanoma pathology
Oncogene Protein v-akt metabolism
bcl-2 Homologous Antagonist-Killer Protein metabolism
bcl-2-Associated X Protein metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
JNK Mitogen-Activated Protein Kinases metabolism
Melanoma drug therapy
Melanoma enzymology
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Taxoids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 13
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 17317842
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-06-2216