Identifizierung und Charakterisierung von molekularen Resistenzmechanismen in Tumorzellen

Abstract

Antitumor drugs mainly act by killing tumor cells via the activation of apoptosis. One characteristic of tumor cells is the evasion of apoptosis. During the course of malign transformation tumor cells generally acquire a resistance against apoptotic stimuli, in addition, resistant cells are selected during chemotherapeutic treatment. Resistance to apoptosis therefore represents a major hurdle in the treatment of tumors with antitumor agents. Therefore the identification and characterization of resistance mechanisms of tumor cells is the first step for the development of strategies that enhance the efficiency of antitumor drugs. The TNF-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent as it induces apoptosis selectively in tumor cells without any cytotoxic effects on normal cells. However many malign tumors are resistant to TRAIL-induced apoptosis. Therefore this project aimed on the identification and the evaluation of molecular mechanisms of TRAIL resistance in tumor cells. In one part of the project the expression of TRAIL-specific receptors was analysed. It could be shown that the expression of the apoptosis-activating TRAIL receptors TRAIL-R1 and TRAIL-R2 relative to the expression of the inhibitory receptors TRAIL-R3 and TRAIL-R4 represent a decisive marker for the TRAIL responsiveness in tumor cells. The importance of the expression of TRAIL-R1 for the TRAIL sensitivity could be highlighted by overexpression of TRAIL-R1 in a TRAIL-resistant cell line and by the finding that TRAIL resistance can be acquired in a TRAIL-sensitive cell line through down-regulation of TRAIL-R1. The second part of the work focused on NF-Kappa B, a transcription factor that regulates the expression of anti-apoptotic genes. It could be shown that constitutive activated NF-Kappa B conferes TRAIL resistance by up-regulation of the anti-apoptotic protein XIAP.