IKK-beta mediates chemoresistance by sequestering FOXO3; a critical factor for cell survival and death

Tezil, Tuğsan and Bodur, Çağrı and Kütük, Özgür and Başağa, Hüveyda (2012) IKK-beta mediates chemoresistance by sequestering FOXO3; a critical factor for cell survival and death. Cellular Signalling, 24 (6). pp. 1361-1368. ISSN 0898-6568

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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.
Item Type: Article
Uncontrolled Keywords: FOXO3; IKK; Chemoresistance; Cell death; Breast cancer
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Engineering and Natural Sciences > Academic programs > Biological Sciences & Bio Eng.
Faculty of Engineering and Natural Sciences
Depositing User: Hüveyda Başağa
Date Deposited: 22 May 2012 15:01
Last Modified: 31 Jul 2019 10:57
URI: https://research.sabanciuniv.edu/id/eprint/19052

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