BIDIRECTIONAL REGULATION OF TELOMERASE ACTIVITY IN A SUBLINE DERIVED FROM HUMAN LUNG ADENOCARCINOMA

Telomerase is active in germline cells and tumor cells, but is either not expressed or is repressed in a majority of somatic cells, The regu lation mechanism of telomerase activity has lately drawn considerable attention for the possible use of telomerase inhibitors for anti-cance r therapy. We analyzed the regulation mechanism of telomerase activity in the human lung adenocarcinoma cell line A549 and its subline A5DC7 which shows impaired tumor phenotypes. Although A549 and A5DC7 cells have similar growth potentials, when cultured in medium supplemented w ith 5% fetal bovine serum A5DC7 cells demonstrated a remarkable negati ve regulation of telomerase activity and telomere shortening. After th e long-term culture, A5DC7 cells showed a large senescent cell-like mo rphology, arrested growth at the 106 population doubling level and ent ered senescence which was demonstrated by expression of the beta-galac tosidase senescence marker. When the serum concentration was raised fr om 5% to 10% for the senescent A5DC7 cells, telomerase reactivation an d telomere lengthening occurred as well as resumption of proliferation ., These results demonstrate that the growth arrest seen in senescent A5DC7 cells is reversible and that telomerase activity is also bi-dire ctionally regulated in A5DC7 cells, an event which could not be observ ed in normal senescent cells. This indicates that stringent telomerase repression and complete growth arrest concomitant with cellular senes cence is collapsed in senescent A5DC7 cells in response to exogenous s ignals;, Our study suggests that cellular senescence progresses and/or is regulated at multiple levels. (C) 1997 Academic Press.