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Matti Narkia

Induction of Ovarian Cancer Cell Apoptosis by 1,25-Dihydroxyvitamin D3 through the Down... - 0 views

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    Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase.
    Jiang F, Bao J, Li P, Nicosia SV, Bai W.
    J Biol Chem. 2004 Dec 17;279(51):53213-21. Epub 2004 Oct 12.
    PMID: 15485861
    doi: 10.1074/jbc.M410395200

    Overall, the study suggests that the down-regulation of telomerase activity by 1,25(OH)2VD3 and the resulting cell death are important components of the response of OCa cells to 1,25(OH)2VD3-induced growth suppression.

    Progressive shortening of telomere associated with cell divisions limits the life span of normal cells and eventually leads to senescence. To become immortal, human cancers including OCa are invariably associated with activation of mechanism that maintains telomere length. Approximately 85-90% of cancers show reactivation of telomerase. The present study shows that telomerase in OCa cells is down-regulated by 1,25(OH)2VD3. Down-regulation of telomerase is due to decreased stability of hTERT mRNA rather than VDRE-mediated transcriptional repression through the putative VDRE present in the regulatory region of the hTERT gene.

    It is known that the inhibition of telomerase may lead to a phenotypic lag during which cells would continue to divide until the point at which the telomeres became critically short. This phenomenon may explain why the apoptotic induction by 1,25(OH)2VD3 needs the treatment for more than 6 days. As mentioned in the results, no detectable shortening of telomeric repeats was observed in parental OVCAR3 cells after 9 days of treatment with 1,25(OH)2VD3 (Fig. 4D). This is likely due to the fact that the short telomere (about 3 kb) in OVCAR3 cells is very close to the minimal length required for survival and that cells with detectably shorter telomere may have been selected against apoptosis. It has been shown that transformed human cells enter crisis once the terminal restriction fragment of the telomere reaches a length of about 4 kb. This is insufficient to protect chro
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