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Telomerase Activity Is Repressed during Differentiation of Maturation-sensitive but not Resistant Human Tumor Cell Lines¹

Laboratories of Developmental Hematopoiesis [J. A., W. H., R. G., M. A. S. M.] and Molecular Medicine [B. M., E. D.] and Genitourinary Oncology Service [E. D., H. I. S.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The effects of induced differentiation on telomerase activity were examined in human acute promyelocytic leukemic (NB4) and human embryonal carcinoma (NTERA-2) cells exposed to all-trans-retinoic acid or hexamethylene bisacetamide. Retinoic acid treatment of NB4 and NTERA-2 cells, and hexamethylene bisacetamide treatment of NTERA-2 cells caused a decline in telomerase activity in differentiation-sensitive but not in resistant clones of these cell lines. Changes in telomerase activity as measured by the PCR-based telomeric repeat amplification protocol assay were noted by 24–72 h of exposure to the inducer, suggesting that its regulation may precede terminal differentiation. The degree of telomerase activity decline was greater in NB4 cells than in NTERA-2 cells, probably reflecting in part a more mature state of NB4 cells after 5 days of exposure to the inducer. Mixing of protein extracts from treated and untreated cells did not suggest the presence of diffusible telomerase inhibitors. Expression of the RNA component of telomerase was also examined in NB4 cells, and its decline correlated with the reduced telomerase activity measured by the telomeric repeat amplification protocol assay during induced differentiation of these tumor cells. Taken together, these findings indicate that telomerase is a regulated enzyme system during induced human tumor cell differentiation, showing an inverse relationship between the degree of differentiation and telomerase activity. These models will be useful to study the regulation and role of telomerase during induced differentiation of human tumor cells.

¹ This work was supported by NIH Grants U19 CA67842-01 (M. A. S. M.), RO1-CA62275-02 (E. D.), and RO1-CA54494-04A1 (E. D.), the Gar Reichman Fund of the Cancer Research Institute (M. A. S. M.), the Byrne Foundation (M. A. S. M.), American Cancer Society Grant DB-47E (E. D.), the Martin Himmel Fund (H. I. S.), the CaPcure Foundation (H. I. S.), and Fondo de Investigación Sanitaria (Spain) Grants 94/5654 (J. A.) and 95/5641 (B. M.).

² To whom requests for reprints should be addressed, at Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Received 1/19/96. Accepted 2/13/96.

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