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 NFkappaB-dependent target genes were also induced. In the resistant cell line, however, only a small number of E2F1-, p53- and NFkappaB-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.
Heikaus
Sebastian
S
Institute of Pathology, Heinrich Heine University Hospital, Moorenstrasse 5, 40225 Duesseldorf, Germany.
Casliskan
Ercan
E
Mahotka
Csaba
C
Gabbert
Helmut Erich
HE
Ramp
Uwe
U
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology*; D015533:Transcriptional Activation
D053221:TNF-Related Apoptosis-Inducing Ligand; D019772:Topotecan