Visual Universitätsmedizin Mainz

Dr. Maja T. Tomicic-Christmann

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Resistance to anticancer drugs: IAPs, DSB repair and the epigenetically regulated markers in GB and CRC

The development of resistance to cytostatic agents is a hard barrier to overcome in the context of tumor therapy. The response of tumor cells to treatment with chemotherapeutic agents, which induce lethal double-strand breaks (DSB), has been (de)regulated at multiple levels. On the one hand, the DNA damage-dependent responses  (DNA damage response, DDR) and the subsequent DSB repair can be increased; on the other hand, the number of survival-promoting or inhibiting apoptotic functions, such as the expression of anti-apoptotic proteins from the family of IAPs (inhibitors of apoptosis proteins) can be strongly activated (Tomicic; Kaina 2013). The activity of cytotoxicity p53 plays a crucial role in this activation. (Tomicic et al. 2005; Tomicic et al. 2010; Tomicic und Kaina 2013).

The focus of our work lies on the anti-apoptotic proteins, Survivin and XIAP, respectively the determination of the cell localization and the potential association with components of DSB repair (primarily a possible co-localization with yH2AX, Rad51  and BRCA2) through genotoxic stress.

The expression of Survivin and XIAP is increased in various types of tumors, including the malignant glioma grade III and IV (glioblastoma); colorectal cancer (CRC), and correlated with the degree of malignancy. Therefore, the two proteins are specific molecular targets that are suitable for a downregulation in tumor cells. In particular, Survivin presents itself as an important resistant marker in the treatment with ionizing radiation, whereby a direct association of the DSB repair via a non-homologous end-to-end link (non-homologous end joining) could be shown. (Reichert et al. 2011).

This association of cytostatics, which are used in these tumor types together with radiation, has not been investigated yet. Our studies are important both to clarify this potential association and to find out how to overcome the resistance of cytostatics through the use of adjuvant therapy. This therapy is based on small molecule inhibitors of Survivin /XIAP and has already been clinically tested. In addition, we are investigating the epigenetic alterations in the promoter methylation of tumor suppressor XAF-1, an opponent of XIAP and Survivin, as a potential prognostic marker for high-grade gliomas.

 

Tomicic M., Meise R., Aasland D., Berte N., Kitzinger R., Krämer O.H., Kaina B., Christmann M. (2015) Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun mediated induction of the BH3-only protein BIMOncotargetDOI: 10.18632/oncotarget.5274


Tomicic M., Aasland D., Naumann S., Meise R., Barckhausen C., Kaina B., Christmann M. (2014) Translesion Polymerase η Is Upregulated by Cancer Therapeutics and Confers Anticancer Drug Resistance. Cancer Res. 74, 5585-5596

 

Tomicic M., Kaina B. (2013) Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim Biophys Acta. 1835, 11-27

 

Reichert S., Rödel C., Mirsch J., Harter P.N., Tomicic M., Mittelbronn M., Kaina B., Rödel F. (2011) Survivin inhibition and DNA double-strand break repair: a molecular mechanism to overcome radioresistance in glioblastoma. Radiother Oncol. 101, 51-58

 

Tomicic M., Christmann M., Kaina B. (2010) Topotecan triggers apoptosis in p53-deficient cells by forcing degradation of XIAP and survivin thereby activating caspase-3 mediated Bid cleavage. Journal Pharmacol Exp Ther. 332, 316-325

 

Tomicic M., Christmann M., Kaina B. (2005) Topotecan-triggered degradation of topoisomerase I is p53-dependent and impacts cell survivalCancer Res. 65, 8920-8926