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 approximately 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 D(3) (1,25(OH)(2) VD)(3)induces OCa cell apoptosis by down-regulating telomerase. Quantitative reverse transcription-PCR analysis shows that 1,25(OH)(2)VD(3) 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) VD(3) decreases the stability of the hTERT mRNA. Stable expression of hTERT in OCa cells decreases their response to 1,25(OH)(2)VD(3)-induced growth suppression. Although the cell cycle progression of these clones stably expressing hTERT is inhibited by 1,25(OH)(2)VD(3) to a similar degree as that of the parental cells, these clones are more resistant to apoptosis induced by 1,25(OH)(2)VD(3) .In contrast to parental cells, which lose proliferation potential after the 1,25(OH)(2)VD(3) treatment, hTERT-expressing clones resume rapid growth after withdrawal of 1,25(OH)(2)VD(3). Overall, the study suggests that the down-regulation of telomerase activity by 1,25(OH)(2)VD(3) and the resulting cell death are important components of the response of OCa cells to 1,25(OH)(2)VD(3)-induced growth suppression.
Department of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612-4799, USA.
Feng
F
Jiang
Junying
J
Bao
Pengfei
P
Li
Santo V
SV
Nicosia
Wenlong
W
Bai
D017209:Apoptosis; D002117:Calcitriol / Q000378:metabolism*; D020134:Catalytic Domain; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D004396:Coloring Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048348:Reverse Transcription; D019098:Telomerase / Q000096:biosynthesis* / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D004396:Coloring Agents; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D019098:Telomerase; C022616:thiazolyl blue; D002117:Calcitriol