Journal
CELLULAR SIGNALLING
Volume 24, Issue 6, Pages 1361-1368Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2012.01.012
Keywords
FOXO3; IKK; Chemoresistance; Cell death; Breast cancer
Categories
Funding
- TUBITAK [109S340]
- Turkish Association for Cancer Research and Control
- Yousef Jameel Scholarship
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Chemotherapeutic drugs proved only 50% successful in breast cancer because of cell type-dependent resistance mechanisms. FOXO3 is known to be involved in the regulation of several cell death-related genes; however, the extent of FOXO3 regulation in chemoresistance is still not fully understood. Here, we show that FOXO3 critically mediates cisplatin chemosensitivity of MCF-7 breast cancer cells which express higher levels of FOXO3 compared to resistant MDA-MB-231 cells. Administration of cisplatin induces apoptosis in MCF-7 cells in a FOXO3-dependent manner as indicated by RNA interference. On the other hand, IKK-beta (I kappa B kinase) appears to inhibit FOXO3 action after cisplatin treatment and promotes chemoresistance in MDA-MB-231 cells. IKK-p directly interacts and sequesters FOXO3 in the cytosol preventing its nuclear localization. Moreover, cisplatin treatment induces autophagosome formation through LC-3 conversion while inhibiting the cleavage of caspase 9 and caspase 3 in MDA-MB-231 cells manipulated to overexpress FOXO3. In brief, our findings demonstrate that in addition to cellular level of active FOXO3, cisplatin chemoresistance is also regulated by IKK-beta sequestration of FOXO3 in cytosol. (C) 2012 Elsevier Inc. All rights reserved.
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