Proteazom İnhibisyonu Ve Şaperon Aracılı Otofaji İnhibisyonu Kombinasyonunun Meme Kanseri Hücrelerinde Apoptoz Ve Otofaji Açısından Değerlendirilmesi

Yılmaz B. (Executive) , Kartal Özer N. , Koçtürk A. S.

TUBITAK Project, 2013 - 2015

  • Project Type: TUBITAK Project
  • Begin Date: April 2013
  • End Date: October 2015

Project Abstract

Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective

anti-cancer therapeutic approach. Among these inhibitors, the first-in-class agent bortezomib has been demonstrated and

actively used in several cancer types in the clinic. On the other hand, alternative inhibitors to bortezomib has been developed

because of its important side effects including neuropathy and the developing resistance against it in some of the cancer types

especially in solid tumors. Carfilzomib, as quite new in the clinic, shows less side effects due to its target-driven effects.

Cancer cells are caused to undergo different types of cell death due to inhibition of different pathways via proteasome inhibition.

Firstly, apoptotic death is aimed but cells may develop resistance because of several degradation mechanisms. Autophagy,

which is higly focused in the literature, is one of these mechanisms. Autophagy has been investigated as macro-, micro- and

chaperone mediated autophagy. There are many studies with autophagy inhibitors showing the decrease in the resistance

development against proteasome inhibition. On the other hand, there are too few work on the role of chaperone mediated

autophagy in this resistance. Therefore this study has been designed to highlight this mechanism and contribute to literature.

Breast cancer is the most frequent reason for the cancer related death in women. Estrogen receptors particularly has important

role in the development and the progression of breast carcinoma. Estrogen receptor is an important prognostic and therapeutic

biomarker in the 75% of breast tumors. Although the tumor growth inducing effects of estrogen has been tried to be blocked by

the therapeutics, 50% of the breast cancer patients do not reply to this treatment after a while and develope de-novo

resistance. There are many studies showing the effect of proteasomal degradation in this developing resistance. Additionally,

ErbB2/HER2 receptor is also a validated target in the clinical therapy of breast cancer and it is known to be degraded by the

proteasome following its ubiquitination.

The aim of this project is to compare the effects of second generation proteasome inhibitor carfilzomib with the clinically used

proteasome inhibitor bortezomib with the combination of chaperone mediated autophagy inhibition. Estrogen receptor

negative/positive and HER2 (human epidermal growth factor) negative/positive cells will be used in the study. There is no

detailed study regarding the use of carfilzomib in breast cancer. On the other hand, the combinational usage of carfilzomib and

bortezomib will be tested to overcome the side effects of bortezomib in the patients. Also usage of carfilzomib instead of

bortezomib and decreased dose of bortezomib in combination with carfilzomib will be evaluated. As another important

approach, proteasome inhibitors and chaperone mediated autophagy inhibition will be tested in combination regarding the cell

death. In this direction, there is no detailed research paper. In this aspect, this study will be extremely unique. On the other

hand, I believe that the results will highlight the future work in my career and will be a source for many new studies.

Keywords: Proteasome, Bortezomib, Carfilzomib, Chaperone Mediated Autophagy, Breast Cancer