Combination treatment with 1alpha,25-dihydroxyvitamin D3 and 9-cis-retinoic acid directly inhibits human telomerase reverse transcriptase transcription in prostate cancer cells.

The vitamin D(3) receptor, which is the nuclear receptor for 1alpha,25-dihydroxyvitamin D(3) (VD(3)), forms a heterodimer with the retinoid X receptor (RXR), which is the nuclear receptor for 9-cis-retinoic acid (9-cis-RA). The heterodimer binds to a specific response element consisting of two directly repeated pairs of motifs, AGGTGA, spaced by three nucleotides [direct repeat (DR) 3] and modulates the expression of VD(3)-responsive genes. Telomerase activity, which is seen in most immortal cells and germ cells, is a complex of enzymes that maintain the length of telomeres. One of the major components of human telomerase, human telomerase reverse transcriptase (hTERT), is the catalytic subunit, and the expression of hTERT might correlate most strongly with telomerase activity. We found that the sequence of 5'-AGTTCATGGAGTTCA-3' (DR3') is similar to that of DR3 in the promoter region of hTERT. Our results showed that the combination of VD(3) and 9-cis-RA inhibited telomerase activity through direct interaction of the heterodimer of vitamin D(3) receptor and RXR with the DR3' sequence in the hTERT promoter as well as the combination of VD(3) and selective RXR ligand did. Also, in vivo data showed that the growth of xenografts in nude mice was inhibited by VD(3) and 9-cis-RA. The results of the present study provide evidence on the molecular mechanism of the inhibition of cell growth by these agents, and they could be novel therapeutic agents for prostate cancer.