Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter

Because the apoptotic pathway is often disrupted in tumor cells, its geneti c restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restr ict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majo rity of malignant gliomas have telomerase activity whereas normal brain cel ls do not. Activation of telomerase is tightly regulated at the transcripti onal level of the telomerase catalytic subunit [human telomerase reverse tr anscriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promot er-driven vector system, an apoptosis-inducible gene may be preferentially restricted to telomerase- or hTERT-positive tumor cells. In this study, we constructed an expression vector consisting of the constitutively active ca spase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-caspase-6) and then investigated its antitumor effect on malignant glioma cells. The ratio nale for using the rev-caspase-6 gene is because it induces apoptosis indep endent of the initiator caspases. We demonstrated that the hTERT/rev-caspas e-6 construct induced apoptosis in hTERT-positive malignant glioma cells, b ut not in hTERT-negative astrocytes, fibroblasts, and alternative lengtheni ng of telomeres cells. In addition, the growth of s.c. tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-caspase-6 cons truct. The present results strongly suggest that the telomerase-specific tr ansfer of the rev-caspase-6 gene under the hTERT promoter is a novel target ing approach for the treatment of malignant gliomas.