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Inhibition of telomerase limits the growth of human cancer cells

Nature Medicine volume 5, pages 1164–1170 (1999)Cite this article

Abstract

Telomerase is a ribonucleoprotein enzyme that maintains the protective structures at the ends of eukaryotic chromosomes, called telomeres. In most human somatic cells, telomerase expression is repressed, and telomeres shorten progressively with each cell division. In contrast, most human tumors express telomerase, resulting in stabilized telomere length. These observations indicate that telomere maintenance is essential to the proliferation of tumor cells. We show here that expression of a mutant catalytic subunit of human telomerase results in complete inhibition of telomerase activity, reduction in telomere length and death of tumor cells. Moreover, expression of this mutant telomerase eliminated tumorigenicity in vivo. These observations demonstrate that disruption of telomere maintenance limits cellular lifespan in human cancer cells, thus validating human telomerase reverse transcriptase as an important target for the development of anti-neoplastic therapies.

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Figure 1: Expression of WT-hTERT and DN-TERT in immortalized cell lines.
Figure 2: Effects of WT-hTERT and DN-hTERT on telomerase activity.
Figure 3: Effects of DN-hTERT expression on telomere length.
Figure 4: Effects of DN-hTERT on cell proliferation.
Figure 5: Expression of DN-hTERT induces apoptosis.

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Acknowledgements

We thank the members of R.A.W. lab for discussions, R. Sexena for assistance with pulse field electrophoresis, and A. Leff and M.A. Mastrangelo for technical assistance. This work was supported in part by Merck and Company (R.A.W.), the US National Cancer Institute (R.A.W.), a Charles E. Culpeper Biomedical Pilot Initiative Grant (R.A.W. and W.C.H.), and a Damon Runyon-Walter Winchell Cancer Research Foundation Postdoctoral Fellowship (W.C.H.), an Anna Fuller Postdoctoral Fellowship (S.A.S.), and a Human Frontiers Postdoctoral Fellowship (R.L.B.). W.C.H. is a Herman and Margaret Sokol postdoctoral fellow. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

Author information

Author notes

  1. Joan H.M. Knoll

    Present address: Section of Genetics and Molecular Medicine, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, 64108, USA

  2. William C. Hahn and Sheila A. Stewart: W.C.H. and S.A.S. contributed equally to this work.

Authors and Affiliations

  1. & Department of Biology, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    William C. Hahn, Sheila A. Stewart, Mary W. Brooks, Elinor Eaton, Akiko Kurachi, Roderick L. Beijersbergen & Robert A. Weinberg

  2. Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts , USA

    William C. Hahn & Matthew Meyerson

  3. Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, 02115, Massachusetts, USA

    William C. Hahn

  4. Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, 02115, Massachusetts, USA

    Matthew Meyerson

  5. Department of Pathology, Cytogenetics Service, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston , 02115, Massachusetts, USA

    Shoshana G. York & Joan H.M. Knoll

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Correspondence to Robert A. Weinberg.

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Hahn, W., Stewart, S., Brooks, M. et al. Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5, 1164–1170 (1999). https://doi.org/10.1038/13495

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