Ph.D. Dissertation Defense: Tuğsan Tezil
  • FENS
  • Ph.D. Dissertation Defense: Tuğsan Tezil

You are here

PROBING THE EFFECT OF IKK ON FOXO3: A REGULATORY MECHANISM OF APOPTOSIS AND AUTOPHAGY IN CHEMORESISTANCE 

Tuğsan TEZİL
Biological Sciences and Bioengineering, Ph.D. Dissertation, 2012 

Thesis Jury:

Prof. Dr. Hüveyda Başağa (Thesis supervisor), Assoc. Prof. Devrim Gözüaçık, Assoc. Prof. O.Uğur Sezerman, Prof. Dr. Canan Atılgan, Asst. Prof. Dilek Telci

Date &Time: July 26th, 2012 – 14:00

Place: FENS G029

Keywords: FOXO3, IKK, apoptosis, autophagy, breast cancer

 

Abstract


Chemotherapeutic drugs in use are only 50% successful in breast cancer treatment due to the chemoresistance mechanisms of cancer cells. FOXO3, a tumor suppressor, is involved in the regulation of several cell death-related genes; however, the extent of FOXO3 regulation in chemoresistance is not fully understood.

In this study our aim was to characterize the potential crosstalk between FOXO3 and NFκB pathway with a special focus on IKK-FOXO3 interaction in chemoresistance mechanism. For this purpose, we characterized chemoresistant (MDA-MB-231)  and chemosensitive  (MCF-7) breast cancer cell lines by paclitaxel (20nM) or cisplatin (30μM) treatments. Administration of 30μM cisplatin induces FOXO3-dependent apoptosis in MCF-7 cells as indicated by RNA interference studies. Following the analysis of NFκB pathway elements by immunoblotting and overexpression studies, we identified the physical interaction between IKKβ and FOXO3 by co-immunoprecipitation. We investigated that IKKβ sequesters FOXO3 in the nucleus promoting chemoresistance in MDA-MB-231 cells. Additionally, imbalance between FOXO3 and IKKβ levels induces autophagy rather than apoptosis in FOXO3 overexpressing MDA-MB-231 cells. We have also studied the effect of p53 on FOXO3 and showed p53-dependent FOXO3 inhibition in colorectal cancer cells. This is the first study describing FOXO3 regulation by IKKβ in detail and showing that FOXO3/IKKβ ratio may influence the cellular decision of apoptosis or autophagy.

In view of the results obtained, NFκB pathway-FOXO3 crosstalk has been discussed and future studies have been proposed. In the light of recent data published, the interaction between FOXO3 and IKKβ is proposed as a target for therapeutic interventions.