IKK-尾 mediates chemoresistance by sequestering FOXO3; A critical factor for cell survival and death

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• 作者：Tugsan Tezil^a ; ^{teziltugsan@su.sabanciuniv.edu} ; Cagri Bodur^a ; ^{bodur@sabanciuniv.edu} ; Ozgur Kutuk^b ; ^{ozgur_kutuk@dfci.harvard.edu} ; Huveyda Basaga^a ; ^{huveyda@sabanciuniv.edu}
• 关键词：FOXO3 ; IKK ; Chemoresistance ; Cell death ; Breast cancer
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：June, 2012
• 卷：24
• 期：6
• 页码：1361-1368
• 文件大小：922 K

摘要

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-尾 (I魏B kinase) appears to inhibit FOXO3 action after cisplatin treatment and promotes chemoresistance in MDA-MB-231 cells. IKK-尾 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-尾 sequestration of FOXO3 in cytosol.