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 regulation mechanism of telomerase activity has lately drawn considerable attention for the possible use of telomerase inhibitors for anti-cancer 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 with 5% fetal bovine serum A5DC7 cells demonstrated a remarkable negative regulation of telomerase activity and telomere shortening. After the long-term culture, A5DC7 cells showed a large senescent cell-like morphology, arrested growth at the 106 population doubling level and entered senescence which was demonstrated by expression of the beta-galactosidase senescence marker. When the serum concentration was raised from 5% to 10% for the senescent A5DC7 cells, telomerase reactivation and 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-directionally regulated in A5DC7 cells, an event which could not be observed in normal senescent cells. This indicates that stringent telomerase repression and complete growth arrest concomitant with cellular senescence is collapsed in senescent A5DC7 cells in response to exogenous signals. Our study suggests that cellular senescence progresses and/or is regulated at multiple levels.