Induction of Ovarian Cancer Cell Apoptosis by 1,25-Dihydroxyvitamin D₃ through the Down-regulation of Telomerase*

The maintenance of telomere length is required for continued cell proliferation, and ∼85–90% of human cancers, including ovarian epithelial cancers (OCa), show high activity of telomerase. In the present study we report that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂ VD)₃induces OCa cell apoptosis by down-regulating telomerase. Quantitative reverse transcription-PCR analysis shows that 1,25(OH)₂VD₃ 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)₂VD₃-induced growth suppression. Although the cell cycle progression of these clones stably expressing hTERT is inhibited by 1,25(OH)₂VD₃ to a similar degree as that of the parental cells, these clones are more resistant to apoptosis induced by 1,25(OH)₂VD₃ .In contrast to parental cells, which lose proliferation potential after the 1,25(OH)₂VD₃ treatment, hTERT-expressing clones resume rapid growth after withdrawal of 1,25(OH)₂VD₃. 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.