Paclitaxel-Induced Nuclear Translocation of FOXO3a in Breast Cancer Cells Is Mediated by c-Jun NH2-Terminal Kinase and Akt

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