A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents

Abstract

Most tumour cells are sensitive to TRAIL-induced apoptosis, but not normal cells; thus, cancer therapy using TRAIL is expected clinically. Several tumour cells are resistant to TRAIL-induced apoptosis, and various mechanisms of such resistance were reported in individual cases. In this study, we established a TRAIL-resistant glioma cell line, which completely lacked TRAIL receptors. In addition, this tumour cell line had wild-type p53 tumour-suppressive gene, suggesting new mechanisms for tumour cells to expand and escape from immune surveillance. The present study further explored the mechanisms that determine the sensitivity to TRAIL. We show that genotoxic agents such as cisplatin, doxorubicin and camptothecin, in addition to UV radiation, can induce TRAIL-R2 on the cell surface of TRAIL receptor-negative tumour cells. Newly synthesised TRAIL-R2 is functional, so apoptosis is effectively induced by TRAIL, but it is significantly inhibited by constitutive expression of dominant-negative p53. In addition, apoptosis induced by pretreatment of genotoxic agents and additional stimulation of TRAIL is efficiently inhibited by either antagonistic anti-TRAIL-R2 antibody or pan-caspase inhibitor z-VAD-FMK. Taken together, these findings suggest that resistance to TRAIL by lack of TRAIL receptors on glioma is restored by genotoxic agents, which support the new strategies for tumour killing by TRAIL-bearing cytotoxic cells in combination with genotoxic treatment.

Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin

“…Cisplatin treatment, in contrast to previously reported findings in other cultured cancer cells (27,29), did not significantly alter the phenotypic expression of the TRAIL functional receptors DR4/DR5 or the decoy receptors DcR1/DcR2 (Fig. 5A).…”

“…2B and 9A). Previous studies have indicated that cytotoxic chemotherapeutic drugs sensitize cultured cancer cells to TRAIL by up-regulation of the receptors DR4/ DR5 (25,27,29,40), enhanced DISC formation/function (26,41,42), or alterations of the phenotypic expression of proapoptotic/antiapoptotic proteins (25,34,43,44) that is paralleled with an overall increase of caspase-8 activation and massive cell death. Our data did not indicate a significant alteration of TRAIL receptor expression in CDDP-treated cells.…”

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

“…Some resistant glioma cell lines could be sensitised by the treatment with the translation inhibitor cycloheximide, implicating a labile inhibitor of TRAIL signalling in the resistance of those cell lines (Rieger et al, 1998;Wu et al, 2000;Hao et al, 2001;Rohn et al, 2001;Fulda et al, 2002a). Lack of surface expression of TRAIL death receptors was reported in one glioma cell line (Arizono et al, 2003). Co-treatment of some resistant lines with chemotherapy drugs, which raised TRAIL receptor levels, enhanced TRAIL sensitivity (Nagane et al, 2000;Rohn et al, 2001;Shinohara et al, 2001;Arizono et al, 2003).…”

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

“…As cancer therapy in the clinic often involves the use of multiple therapeutic regimens, it was of interest to determine if HGS-ETR1 in combination with commonly used anticancer agents could enhance HGS-ETR1 activity in vitro and in vivo. Previous studies have shown that chemotherapeutic agents enhance TRAIL-induced cell killing of various tumour cells in vitro and in vivo (Naka et al, 2002;Arizono et al, 2003;Ray and Almasan, 2003;Singh et al, 2003). Combination treatment with chemotherapeutic agents in vitro also enhance murine TRAIL-R1 and TRAIL-R2 agonistic antibody-induced cell killing (Ohtsuka et al, 2003), and combination of a murine TRAIL-R2 antibody with adriamycin or paclitaxel showed greater inhibition of tumour growth compared to antibody alone in a breast cancer model in vivo .…”