Probing the effect of IKK on FOXO3 aregulatory mechanism of apoptosis and autophagy in chemoresistance
Tezil, Tuğsan (2012) Probing the effect of IKK on FOXO3 aregulatory mechanism of apoptosis and autophagy in chemoresistance. [Thesis]
Official URL: http://192.168.1.20/record=b1499075 (Table of Contents)
Breast cancer chemotherapeutics are only 50% successful due to chemoresistance mechanism of cancer cells. FOXO3, a tumor suppressor protein, is involved in the regulation of several cell death-related genes; however, the extent of FOXO3 regulation in chemoresistance mechanism is not fully understood. In this study our aim was to characterize the potential crosstalk between FOXO3 and NF-kappaB pathway with a special focus on IKK-FOXO3 interaction in relation to chemoresistance mechanism. For this purpose, we have used chemoresistant (MDAMB- 231) and chemosensitive (MCF-7) breast cancer cell lines treated with paclitaxel (20nM) or cisplatin (30uM). Administration of 30uM cisplatin induced FOXO3- dependent apoptosis in MCF-7 cells as indicated by RNA interference studies. Following the analysis of NF-kappaB pathway elements by immunoblotting and overexpression studies, we identified the physical interaction between IKK-beta and FOXO3 by co-immunoprecipitation. We have shown that IKK-beta sequesters FOXO3 in the nucleus promoting chemoresistance in MDA-MB-231 cells. Additionally, imbalance between FOXO3 and IKK-beta levels induced autophagy rather than apoptosis in FOXO3 overexpressing MDA-MB-231 cells. We have also studied the effect of p53 on FOXO3 levels and showed p53-dependent FOXO3 inhibition in colorectal cancer cells. This is the first study describing FOXO3 regulation by IKK-beta in detail and showing that FOXO3/IKK-beta ratio may influence the cellular decision of apoptosis or autophagy. In view of the results obtained, NF-kappaB pathway-FOXO3 crosstalk has been discussed and the interaction between FOXO3 and IKK-beta is proposed as a target for therapeutic intervention.
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