Sensitivity to TRAIL/APO-2L-mediated apoptosis in human renal cell carcinomas and its enhancement by topotecan

TRAIL (APO-SL) is a newly identified member of the TNF family and induces a poptosis in cancer cells without affecting most non-neoplastic cells, both in vitro and in vivo. Our study focused on the expression and function of T RAIL and its receptors in renal cell carcinoma (RCC) cell lines of all majo r 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 in of 16 RCC cell lines . Remarkably, five of six TRAIL-resistant RCC cell lines exhibited high lev els of TRAIL expression. Topotecan, a novel topoisomerase I inhibitor, indu ced upregulation of TRAIL-RS as well as downregulation of TRAIL. Neutraliza tion of TRAIL with recombinant soluble TRAIL-R1-Fc and TRAIL-R2-Fc failed t o inhibit topotecan-induced apoptosis indicating that topotecan-induced cel l death can occur in a TRAIL-independent fashion. However, exposure to topo tecan resulted in an enhancement of TRAIL-induced apoptosis in all primaril y TRAIL-resistant RCC cell lines. This synergistic effect of cotreatment wi th Topotecan and TRAIL may provide the basis for a new therapeutic approach to induce apoptosis in otherwise unresponsive RCC.