Probing the effect of IKK on FOXO3: a regulatory mechanism of apoptosis and autophagy in chemoresistance

Tezil, Tuğsan (2012) Probing the effect of IKK on FOXO3: a regulatory mechanism of apoptosis and autophagy in chemoresistance. [Thesis]

[thumbnail of TugsanTezil_440926.pdf] PDF

Download (16MB)


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.
Item Type: Thesis
Uncontrolled Keywords: FOXO3. -- IKK. -- Apoptosis. -- Autophagy. -- Breast cancer. -- Inhibitor kappa-B kinase. -- Forkhead box O3 -- Apoptoz. -- Apoptozis. -- Otofaji. -- Meme kanseri. -- İnhibitör kappa-B kinaz.
Subjects: T Technology > TA Engineering (General). Civil engineering (General) > TA164 Bioengineering
Divisions: Faculty of Engineering and Natural Sciences > Academic programs > Biological Sciences & Bio Eng.
Faculty of Engineering and Natural Sciences
Depositing User: IC-Cataloging
Date Deposited: 04 Feb 2015 10:15
Last Modified: 26 Apr 2022 10:04

Actions (login required)

View Item
View Item