Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells.
Telomerase is a promising target for human cancer gene therapy. Its inhibition allows telomere shortening to occur in cancer cells, which in turn is thought to trigger delayed senescence and/or apoptosis. We tested whether telomerase inhibition might have additional, immediate effects on tumor cell growth. Ovarian cancer cell lines with widely differing telomere lengths were efficiently transduced with an adenovirus expressing a ribozyme directed against the T motif of the catalytic subunit of human telomerase, hTERT. Three days after transduction, telomerase activity was significantly reduced and massive cell loss was induced in mass cultures from all four ovarian cancer cell lines tested, whereas transduction of telomerase-negative human fibroblasts did not attenuate their growth. The kinetics of induction of cell death in cancer cells was not significantly dependent on telomere length, and telomeres did not shorten measurably before the onset of apoptosis. The data suggest the existence of a "fast-track" mechanism by which diminution of telomerase can interfere with cancer cell growth and induce cell death, presumably by apoptosis. This phenomenon might be a consequence of the telomere capping function provided by telomerase in tumor cells. Uncapping of telomeres by ribozyme-mediated inhibition of telomerase bears therapeutic potential for ovarian cancer.
Saretzki
G
G
Department of Gynecology, University Hospital, Freiburg, Germany.
Ludwig
A
A
von Zglinicki
T
T
Runnebaum
I B
IB
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D020134:Catalytic Domain / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology*; D016337:RNA, Catalytic / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; D016337:RNA, Catalytic; D019098:Telomerase