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Responses of human cancer cells to telomerase interference
Author(s) -
Blackburn Elizabeth Helen,
Li Shang,
Xu Lifeng
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a152-b
Subject(s) - telomerase , telomere , rna , gene knockdown , telomerase rna component , small interfering rna , telomerase reverse transcriptase , ribonucleoprotein , dna , microbiology and biotechnology , small hairpin rna , cancer cell , biology , rna interference , cancer research , cancer , cell culture , chemistry , biochemistry , genetics , gene
The ribonucleoprotein telomerase is highly active in many human malignancies, and a potential target for cancer therapy. In synthesizing telomeric DNA, telomerase copies a short template sequence within its RNA moiety, and altering this template leads to mutant telomeric DNA incroporation. We developed a novel approach that combines short interfering RNA (siRNA or shRNA) knockdown of the endogenous wild‐type human telomerase RNA (hTer) with expression of a mutant‐template telomerase RNA hTer (MT‐hTer). Such combination MT‐hTer/siRNA constructs induce rapid, functional‐telomerase‐dependent telomere uncapping and a DNA damage response, and inhibition of cell proliferation, in multiple human cancer cell lines. Telomerase functions in cancer maintenance include replenishing telomeric DNA and maintaining cell immortality. However, human cancer cells also responded rapidly to abrupt depletion of telomerase RNA by rapid and distinct cellular/transcriptional responses, despite no obvious bulk telomere shortening or telomere uncapping. Examination of the metastatic potential of human melanoma cells has shown that knock‐down of telomerase RNA reduces metastases in an in vivo animal model.