Die Rolle der Proteindisulfidisomerase ERp57 in der Chemoresistenz des Nierenzellkarzinoms

The impact of the proteine disulfite isomerase ERp57 in chemoresistance of renal cell carcinoma

by Olga Katzendorn
Doctoral thesis
Date of Examination:2019-03-21
Date of issue:2019-03-14
Advisor:Prof. Dr. Hassan Dihazi
Referee:Prof. Dr. Hassan Dihazi
Referee:Prof. Dr. Henning Urlaub
Persistent Address: http://dx.doi.org/10.53846/goediss-7342

 

 

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Abstract

English

It is well-known that renal cell carcinoma is resistant to conventional chemotherapeutic drugs. In the past serious investigation has been made to understand the underlying pathomechanisms. To analyse the mechanism of resistance to a classical chemotherapeutic drug in renal cell carcinoma cell lines, two commercial renal carcinoma cell lines, A498 and Caki-2, were treated with cisplatin and differentially expressed proteins were identified. The Caki-2 cell line was sensitive to treatment with Cisplatin, whereas the A489 cell line was not. Proteome changes after treatment with cisplatin have been shown in both cell lines. In former studies two statistically significant upregulated proteins in A498 cells after treatment with cisplatin were associated with chemoresistance. Further investigation will be necessary to elucidate whether these proteins are key players in resistance of renal cell carcinoma. Furthermore we showed upregulation of proteins being part of the „unfolded protein response“ (UPR). The UPR is activated in order to decrease ER-stress which is provoked by the accumulation of nascent proteins in the ER under stressful conditions. ER stress as well as proteins connected to the UPR, like the chaperons ERp57 or GRP78, have been linked to chemoresistance and cancer. ERp57 is an ER stress protein which displayed upregulation in A498 cells and downregulation in Caki-2 cells after treatment with cisplatin. To investigate its role in chemoresistance, we downregulated and upregulated its expression in both cell lines. We could not prove a key role in chemoresistance, whereas it has to be assumed that this protein is a crucial player in the regulation of cellular homeostasis. Further investigation will be needed to prove this assumption. Moreover, we could not confirm a positive effect of ERp57 on cell proliferation as described earlier.
Keywords: chemoresistance; erp57; renal cell carcinoma; ER-stress
 
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