Sensitivity to TRAIL/APO-2L-mediated apoptosis in human renal cell carcinomas and its enhancement by topotecan.
TRAIL (APO-2L) is a newly identified member of the TNF family and induces apoptosis in cancer cells without affecting most non-neoplastic cells, both in vitro and in vivo. Our study focused on the expression and function of TRAIL and its receptors in renal cell carcinoma (RCC) cell lines of all major histological types. Here, we demonstrate that all RCC cell lines express TRAIL as well as the death-inducing receptors TRAIL-R1 (DR4) and TRAIL-R2 (Killer/DR5). Exposure to TRAIL induced apoptosis in 10 of 16 RCC cell lines. Remarkably, five of six TRAIL-resistant RCC cell lines exhibited high levels of TRAIL expression. Topotecan, a novel topoisomerase I inhibitor, induced upregulation of TRAIL-R2 as well as downregulation of TRAIL. Neutralization of TRAIL with recombinant soluble TRAIL-R1-Fc and TRAIL-R2-Fc failed to inhibit topotecan-induced apoptosis indicating that topotecan-induced cell death can occur in a TRAIL-independent fashion. However, exposure to topotecan resulted in an enhancement of TRAIL-induced apoptosis in all primarily TRAIL-resistant RCC cell lines. This synergistic effect of cotreatment with Topotecan and TRAIL may provide the basis for a new therapeutic approach to induce apoptosis in otherwise unresponsive RCC.
Déjosez
M
M
Institute of Pathology, Heinrich Heine University, D-40225 Duesseldorf, Germany.
Ramp
U
U
Mahotka
C
C
Krieg
A
A
Walczak
H
H
Gabbert
H E
HE
Gerharz
C D
CD
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016158:Genes, p53; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D019772:Topotecan