Differential gene expression in anticancer drug- and TRAIL-mediated apoptosis in renal cell carcinomas

Renal cell carcinomas (RCC) exhibit marked differences in susceptibility towards anticancer drug- and TRAIL-induced apoptosis. However, the underlying mechanisms determining apoptosis-sensitivity or -resistance are not well understood. The purpose of this study was to compare gene expression patterns induced by DNA-damage- and death receptor-induced apoptosis and to detect differentially expressed genes responsible for differences in apoptosis-susceptibility. Therefore, we performed a comparative cDNA-array analysis in an apoptosis-resistant and an apoptosis-sensitive RCC cell line. In the sensitive cell line an upregulation of multiple E2F1- and p53-inducible proapaptotic and cell-cycle regulating target genes by Topotecan as well as TRAIL was observed. Interestingly, several antiapoptotic NFκB-dependent target genes were also induced. In the resistant cell line, however, only a small number of E2F1-, p53- and NFκB-dependent target genes were differentially regulated. Conclusively, anticancer drug- as well as TRAIL-sensitivity go along with an upregulation of multiple proapoptotic genes. In contrast, the mechanisms of apoptosis-resistance are—at least in part—located upstream of gene induction and seem not to depend upon upregulation of de-novo-synthesized antiapoptotic genes. Conclusively, the proapoptotic stimuli are confronted with a cellular context which allows apoptosis to be conducted—in the sensitive cell line—or not—in the resistant cell line. Electronic Supplementary Material The online version of this article (doi: ) contains supplementary material, which is available to authorized users. Sebastian Heikaus and Ercan Casliskan contributed equally to this work. This work was supported by the ’Deutsche Forschungsgemeinschaft (DFG).