Cell cycle-specific changes in hTERT promoter activity in normal and cancerous cells in adenoviral gene therapy: A promising implication of telomerase-dependent targeted cancer gene therapy

  • Authors:
    • Yoshiteru Murofushi
    • Satoshi Nagano
    • Junichi Kamizono
    • Tomoyuki Takahashi
    • Hisayoshi Fujiwara
    • Setsuro Komiya
    • Toyojiro Matsuishi
    • Ken-ichiro Kosai
  • View Affiliations

  • Published online on: September 1, 2006     https://doi.org/10.3892/ijo.29.3.681
  • Pages: 681-688
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Abstract

Based on the finding that telomerase is reactivated solely in cancer cells, the human telomerase reverse transcriptase (hTERT) promoter has recently been used to target cancer cells by gene therapy. The recent, surprising observation that telomerase is physiologically activated even in normal somatic cells during S-phase has raised concerns as to the safety of this methodology. To clarify this issue, the present study carefully examined the changes in endogenous telomerase activities, hTERT mRNA expression, and hTERT promoter-based transgene expression in normal and cancer cells at synchronized phases of the cell cycle. Telomerase activity and hTERT expression were detected at variable, but relatively high, levels in all 12 cancer cell lines, while both were undetectable in the 11 normal cell lines. In HepG2 cancer cells, the highest levels of hTERT expression and telomerase activity, seen in the G1/S- and S-phases, were 2-3-fold higher than the lowest levels of both, observed in G0-phase and during asynchronization. No hTERT expression or telomerase activitiy could be detected in normal WI-38 fibroblasts at any phase of the cell cycle, including S-phase. Consequently, activity of the shorter hTERT promoter, which was transferred into HepG2 cancer cells via adenovirus transduction, was stronger than that of the longer hTERT promoter at all phases and that of two representatives of ubiquitously strong promoters, at both S-phase and asynchronization, but not at G0-phase. In contrast, neither of hTERT promoters induced detectable transgene expressions in normal WI-38 cells at any cell cycle phase, including S-phase. These results, particularly the lack of problematic levels of S-phase-specific activation of hTERT promoters in normal cells, have promising implications for hTERT promoter-based targeted gene therapy of cancer.

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September 2006
Volume 29 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Murofushi, Y., Nagano, S., Kamizono, J., Takahashi, T., Fujiwara, H., Komiya, S. ... Kosai, K. (2006). Cell cycle-specific changes in hTERT promoter activity in normal and cancerous cells in adenoviral gene therapy: A promising implication of telomerase-dependent targeted cancer gene therapy. International Journal of Oncology, 29, 681-688. https://doi.org/10.3892/ijo.29.3.681
MLA
Murofushi, Y., Nagano, S., Kamizono, J., Takahashi, T., Fujiwara, H., Komiya, S., Matsuishi, T., Kosai, K."Cell cycle-specific changes in hTERT promoter activity in normal and cancerous cells in adenoviral gene therapy: A promising implication of telomerase-dependent targeted cancer gene therapy". International Journal of Oncology 29.3 (2006): 681-688.
Chicago
Murofushi, Y., Nagano, S., Kamizono, J., Takahashi, T., Fujiwara, H., Komiya, S., Matsuishi, T., Kosai, K."Cell cycle-specific changes in hTERT promoter activity in normal and cancerous cells in adenoviral gene therapy: A promising implication of telomerase-dependent targeted cancer gene therapy". International Journal of Oncology 29, no. 3 (2006): 681-688. https://doi.org/10.3892/ijo.29.3.681