Inhibition of telomerase limits the growth of human cancer cells.
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.
Hahn
W C
WC
Whitehead Institute for Biomedical Research, Cambridge Center, Department of Biology, Massachusetts Institute of Technology, Cambridge Massachusetts 02142, USA.
Stewart
S A
SA
Brooks
M W
MW
York
S G
SG
Eaton
E
E
Kurachi
A
A
Beijersbergen
R L
RL
Knoll
J H
JH
Meyerson
M
M
Weinberg
R A
RA
D017209:Apoptosis; D001943:Breast Neoplasms; D020134:Catalytic Domain / Q000235:genetics; D002455:Cell Division; D003110:Colonic Neoplasms; D004268:DNA-Binding Proteins; D015195:Drug Design; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D009154:Mutation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000517:prevention & control*; D010051:Ovarian Neoplasms; D012313:RNA; D012190:Retroviridae / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016615:Telomere / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018894:Reverse Transcriptase Inhibitors; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase