Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 51, Pages 53213-53221Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M410395200
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The maintenance of telomere length is required for continued cell proliferation, and similar to85-90% of human cancers, including ovarian epithelial cancers (OCa), show high activity of telomerase. In the present study we report that 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)VD3) induces OCa cell apoptosis by down-regulating telomerase. Quantitative reverse transcription-PCR analysis shows that 1,25(OH)(2)VD3 decreases the level of human telomerase reverse transcriptase ( hTERT) mRNA, the catalytic subunit of telomerase. The decrease is not due to transcriptional repression through the putative vitamin D response element present in the 5' regulatory region of hTERT gene. Instead, 1,25(OH)(2)VD3 decreases the stability of the hTERT mRNA. Stable expression of hTERT in OCa cells decreases their response to 1,25(OH)(2)VD3-induced growth suppression. Although the cell cycle progression of these clones stably expressing hTERT is inhibited by 1,25(OH)(2)VD3 to a similar degree as that of the parental cells, these clones are more resistant to apoptosis induced by 1,25(OH)(2)VD3. In contrast to parental cells, which lose proliferation potential after the 1,25(OH)(2)VD3 treatment, hTERT-expressing clones resume rapid growth after withdrawal of 1,25(OH)(2)VD3. Overall, the study suggests that the down-regulation of telomerase activity by 1,25(OH)(2)VD3 and the resulting cell death are important components of the response of OCa cells to 1,25(OH)(2)VD3-induced growth suppression.
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