This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mhaidat, N. M. Articles by Hersey, P. Search for Related Content PubMed PubMed Citation Articles by Mhaidat, N. M. Articles by Hersey, P.

---

Cell Cycle, Cell Death, and Senescence

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

¹ Immunology and Oncology Unit, David Maddison Clinical Sciences Building, Newcastle, New South Wales, Australia and ² Cancer Research Center at the University of Newcastle, Callaghan, New South Wales, Australia

Requests for reprints: Peter Hersey or Xu Dong Zhang, Immunology and Oncology Unit, Room 443, David Maddison Clinical Sciences Building, corner King and Watt Streets, Newcastle, New South Wales 2300, Australia. Phone: 61-2-49-236828; Fax: 61-2-49-236184. E-mail: Peter.Hersey{at}newcastle.edu.au

Our previous studies showed that docetaxel-induced apoptosis of human melanoma cells was dependent on the activation of the c-jun NH₂-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 PKC and PKC isoforms. Activation of PKC was most marked in docetaxel-resistant cells and paralleled the activation of the ERK1/2 pathway. Inhibition of PKC 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 ß-tubulin class III, a molecular target of docetaxel, coimmunoprecipitated with PKC and colocalized in confocal microscopic studies. In contrast to PKC, high levels of activated PKC were associated with activation of the JNK pathway and sensitivity to docetaxel. Activation of PKC seemed to be upstream of JNK because inhibition of PKC by small interfering RNA abrogated activation of the JNK pathway. Although PKC 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. PKC was associated with prosurvival signaling through ERK, whereas PKC was associated with proapoptotic responses through JNK activation. (Mol Cancer Res 2007;5(10):1073–81)