ANTISENSE TELOMERASE TREATMENT - INDUCTION OF 2 DISTINCT PATHWAYS, APOPTOSIS AND DIFFERENTIATION

Telomerase, the enzyme that elongates telomeric DNA (TTAGGG)(n), may b e involved in cellular immortality and oncogenesis. To investigate the effect of inhibition of telomerase on tumor cells, we transfected the antisense vector against the human telomerase RNA into human malignan t glioma cells exhibiting telomerase activity. After 30 doublings, som e subpopulations of transfectants expressed a high level of interleuki n-lp-converting enzyme (ICE) protein and underwent apoptosis. In contr ast, other subpopulations also showed enhanced ICE protein but escaped from apoptotic crisis and continued to grow, although their DNA synth esis, invasive ability, and tumorigenicity in nude mice were significa ntly reduced. Surviving cells demonstrated increased expression of gli al fibrillary acidic protein and decreased motility, consistent with a more differentiated state. These cells also contained enhanced expres sion of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27. Tr eatment of surviving nonapoptotic cells with antisense oligonucleotide s against p27, but not p21, induced apoptotic cell death, suggesting t hat p27 may have protected differentiating glioma cells from apoptosis . These data show that treatment with antisense telomerase inhibits te lomerase activity and subsequently induces either apoptosis or differe ntiation. Regulation of these two distinct pathways may be dependent o n the expression of ICE or CDKIs.-Kondo, S., Tanaka, Y., Kondo, Y., Hi tomi, M., Barnett, G. H., Ishizaka, Y., Liu, J., Haqqi, T., Nishiyama, A., Villeponteau, B., Cowell, J. K., Barna, B. P. Antisense telomeras e treatment: induction of two distinct pathways, apoptosis and differe ntiation.