Regulation of Docetaxel-Induced Apoptosis of Human Melanoma Cells by Different Isoforms of Protein Kinase C

• Published in: Molecular cancer research 2007-10, Vol.5 (10), p.1073-1081
• Main Authors: Mhaidat, Nizar M, Thorne, Rick F, Zhang, Xu Dong, Hersey, Peter
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Cell Line, Tumor; Docetaxel; ERK1/2; Humans; Isoenzymes - metabolism; JNK; MAP Kinase Kinase 4 - metabolism; Melanoma; Melanoma - enzymology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; PKCδ; PKCε; Protein Kinase C-delta - metabolism; Protein Kinase C-epsilon - metabolism; Skin Neoplasms - enzymology; Taxoids - pharmacology; Tubulin - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-07-0059

Our previous studies showed that docetaxel-induced apoptosis of human melanoma cells was dependent on the activation of the c-jun NH 2 -terminal kinase (JNK) signaling pathway but was inhibited by the extracellular signal–regulated kinase (ERK)-1/2 pathway. However, the mechanisms by which these pathways were modulated by docetaxel were not clear. We report here that docetaxel induces activation of protein kinase C (PKC) signaling differentially through PKCε and PKCδ isoforms. Activation of PKCε was most marked in docetaxel-resistant cells and paralleled the activation of the ERK1/2 pathway. Inhibition of PKCε by small interfering RNA molecules resulted in down-regulation of phosphorylated ERK1/2 and sensitization of cells to docetaxel-induced apoptosis. Experiments also showed that β-tubulin class III, a molecular target of docetaxel, coimmunoprecipitated with PKCε and colocalized in confocal microscopic studies. In contrast to PKCε, high levels of activated PKCδ were associated with activation of the JNK pathway and sensitivity to docetaxel. Activation of PKCδ seemed to be upstream of JNK because inhibition of PKCδ by small interfering RNA abrogated activation of the JNK pathway. Although PKCδ could be activated in resistant cells, downstream activation of JNK and c-Jun did not occur. In summary, these results suggest that the outcome of docetaxel-induced apoptotic events in human melanoma cells depends on their PKC isoform content and signaling responses. PKCε was associated with prosurvival signaling through ERK, whereas PKCδ was associated with proapoptotic responses through JNK activation. (Mol Cancer Res 2007;5(10):1073–81)