title: Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt.
abstract: 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.
authors.affiliation: Cancer Research UK Labs, Department of Cancer Medicine, London.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sunters
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Madureira
authors.forename: Karen M
authors.initials: KM
authors.lastname: Pomeranz
authors.forename: Muriel
authors.initials: M
authors.lastname: Aubert
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
authors.forename: Boudewijn M T
authors.initials: BM
authors.lastname: Burgering
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C499517:FOXO3 protein, human