Telomere shortening and apoptosis in telomerase-inhibited human tumor cells

  1. Xiaoling Zhang,
  2. Vernon Mar,
  3. Wen Zhou,
  4. Lea Harrington, and
  5. Murray O. Robinson
  1. Department of Cancer Biology, Amgen, Thousand Oaks, California 91320 USA; Amgen Institute/Ontario Cancer Institute, Toronto, Ontario M5G2C1 Canada

Abstract

Despite a strong correlation between telomerase activity and malignancy, the outcome of telomerase inhibition in human tumor cells has not been examined. Here, we have addressed the role of telomerase activity in the proliferation of human tumor and immortal cells by inhibiting TERT function. Inducible dominant-negative mutants of hTERT dramatically reduced the level of endogenous telomerase activity in tumor cell lines. Clones with short telomeres continued to divide, then exhibited an increase in abnormal mitoses followed by massive apoptosis leading to the loss of the entire population. This cell death was telomere-length dependent, as cells with long telomeres were viable but exhibited telomere shortening at a rate similar to that of mortal cells. It appears that telomerase inhibition in cells with short telomeres lead to chromosomal damage, which in turn trigger apoptotic cell death. These results provide the first direct evidence that telomerase is required for the maintenance of human tumor and immortal cell viability, and suggest that tumors with short telomeres may be effectively and rapidly killed following telomerase inhibition.

Keywords

Footnotes

  • Corresponding author.

  • E-MAIL mrobinso{at}amgen.com; FAX (805) 447-1982.

    • Received June 4, 1999.
    • Accepted August 3, 1999.
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