TELOMERASE ACTIVITY IS REPRESSED DURING DIFFERENTIATION OF MATURATION-SENSITIVE BUT NOT RESISTANT HUMAN TUMOR-CELL LINES

The effects of induced differentiation on telomerase activity were exa mined in human acute promyelocytic leukemic (NB4) and human embryonal carcinoma (NTERA-2) cells exposed to all-balls-retinoic acid or hexame thylene bisacetamide. Retinoic acid treatment of NB4 and NTERA-2 cells , and hexamethylene bisacetamide treatment of NTERA-2 cells caused a d ecline in telomerase activity in differentiation-sensitive but not in resistant clones of these cell lines. Changes in telomerase activity a s measured by the PCR-based telomeric repeat amplification protocol as say were noted by 24-72 h of exposure to the inducer, suggesting that its regulation may precede terminal differentiation. The degree of tel omerase activity decline was greater in NB4 cells than in NTERA-2 cell s, probably reflecting in part a more mature state of NB4 cells after 5 days of exposure to the inducer. Mixing of protein extracts from tre ated and untreated cells did not suggest the presence of diffusible te lomerase inhibitors. Expression of the RNA component of telomerase was also examined in NB4 cells, and its decline correlated,vith the reduc ed telomerase activity measured by the telomeric repeat amplification protocol assay during induced differentiation of these tumor cells. Ta ken together, these findings indicate that telomerase is a regulated e nzyme system during induced human tumor cell differentiation, showing an inverse relationship between the degree of differentiation and telo merase activity. These models will be useful to study the regulation a nd role of telomerase during induced differentiation of human tumor ce lls.