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Paclitaxel-InducedNuclear Translocationof FOXO3a in BreastCancer Cells IsMediated by c-JunNH2-Terminal Kinaseand Akt Andrew SuntersPatrícia A. MadureiraKaren M. Pomeranz2006 год

Paclitaxel-Induced Nuclear Translocation of FOXO3a in Breast Cancer Cells Is Mediated by c-Jun NH2-Terminal Kinase and Akt
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Страница публикацииПубликация в OpenAlex
Аннотация: 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. (Cancer Res 2006; 66(1): 212-20)
Год издания: 2006
Авторы: Andrew Sunters, Patrícia A. Madureira, Karen M. Pomeranz, Muriel Aubert, Jan J. Brosens, Simon J. Cook, Boudewijn Burgering, R. Charles Coombes, Eric W.‐F. Lam
Издательство: American Association for Cancer Research
Источник: Cancer Research
Ключевые слова: FOXO transcription factor regulation, Reproductive Biology and Fertility, PARP inhibition in cancer therapy
Другие ссылки: Cancer Research (HTML)
PubMed (HTML)