Zur Rolle des Co-Chaperons BAG-1 im Glioblastoma-multiforme-Zellkulturmodell

Role of Co-Chaperone BAG-1 in Glioma

by Michael Müther
Doctoral thesis
Date of Examination:2016-08-01
Date of issue:2016-07-15
Advisor:Prof. Dr. Pawel Kermer
Referee:PD Dr. Florian Stockhammer
Referee:Prof. Dr. Rainer Mausberg
Persistent Address: http://dx.doi.org/10.53846/goediss-5741

 

 

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Abstract

English

Glioblastoma multiforme (GBM) is one of the most malignant brain neoplasias and the most common primary brain tumor in adults with a very poor prognosis. Many molecular pathologies have been found to account for GBM growth. BAG-1 (bcl-2 associated athanogene 1) is a multifunctional protein. As a member of the co-chaperone family it helps stabilize misfolded proteins and affects various cellular functions and cancer related molecular pathways. Malignancies commonly show high levels of BAG-1 protein. Until now less is known about BAG-1 in GBM. Methods: BAG-1 protein level was down-regulated in established GBM cell lines G112, U251 and U87G by using siRNA transfection. Proliferation was assessed by crystal violet and WST-1 proliferation assays. Toxicity was measured using ToxiLight® Bioassay. Flow Cytometry was used to investigate cell cycle changes. Experimental ionizing radiation was applied for testing radiosensitivity. Autophagy and proteasomal function were evaluated using LC3-II Western Blotting and proteasome assays. Results: BAG-1 significantly reduces GBM growth. This effect becomes more obvious in stress conditions such as serum starvation. Cytotoxicity and cell cycle distribution are not significantly affected by BAG-1 siRNA transfection. BAG-1 protein level does not affect radiosensitivity in GBM cells. BAG-1 increases the macroautphagic flux, no significant impact on proteasomal function was found. Conslusion: To improve current therapies it is becoming increasingly important to draw a most precise picture of GBM pathology. For a long time BAG-1 was thought to be an anti-apoptotic protein. In this work BAG-1 reduces GBM growth most likely by sensitizing towards apoptosis. The role of protein degradation mechanisms in GBM is poorly understood. This work provides first data on the impact of BAG-1 on autophagy and proteasomal function in GBM. Further work needs to be done to evaluate the role of BAG-1 in GBM diagnostics and therapy.
Keywords: Glioma; BAG-1; Autophagy; Proteasomal Function; Co-Chaperone
Schlagwörter: Glioblastoma multiforme; BAG-1; Autophagie; Proteasomale Funktion; Co-Chaperon
 
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