Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt

Andrew Sunters, Patricia A Madureira, Karen M Pomeranz, Muriel Aubert, Jan J Brosens, Simon J Cook, Boudewijn M T Burgering, R Charles Coombes, Eric W-F Lam

Research output: Contribution to journalArticlepeer-review


The microtubule-targeting compound paclitaxel is often used in the treatment of endocrine-resistant or metastatic breast cancer. We have previously shown that apoptosis of breast cancer cells in response to paclitaxel is mediated by induction of FOXO3a expression, a transcription factor downstream of the phosphatidylinositol-3-kinase/Akt signaling pathway. To further investigate its mechanism of action, we treated MCF-7 cells with paclitaxel and showed a dose-dependent increase in nuclear localization of FOXO3a, which coincided with decreased Akt signaling but increased c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) activity. Flow cytometry revealed that paclitaxel-induced apoptosis of MCF-7 cells and of other paclitaxel-sensitive breast cancer cell lines was maintained in the presence of inhibitors of p38 (SB203580) or mitogen-activated protein/ERK kinase 1 signaling (PD98059) but abrogated when cells were treated with the JNK1/2 inhibitor SP600125. SP600125 reversed Akt inhibition and abolished FOXO3a nuclear accumulation in response to paclitaxel. Moreover, conditional activation of JNK mimicked paclitaxel activity and led to dephosphorylation of Akt and FOXO3a. Furthermore, mouse embryonic fibroblasts (MEF) derived from JNK1/2 knockout mice displayed very high levels of active Akt, and in contrast to wild-type MEFs, paclitaxel treatment did not alter Akt activity or elicit FOXO3a nuclear translocation. Taken together, the data show that cell death of breast cancer cells in response to paclitaxel is dependent upon JNK activation, resulting in Akt inhibition and increased FOXO3a activity.

Original languageEnglish
Pages (from-to)212-220
Number of pages9
JournalCancer Research
Issue number1
Publication statusPublished - 5 Jan 2006


  • Antineoplastic Agents, Phytogenic/pharmacology
  • Apoptosis/drug effects
  • Breast Neoplasms/drug therapy
  • Cell Line, Tumor
  • Cell Nucleus/metabolism
  • Enzyme Activation
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors/biosynthesis
  • Humans
  • JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 9/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Paclitaxel/pharmacology
  • Phosphatidylinositol 3-Kinases/antagonists & inhibitors
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors
  • Signal Transduction


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