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

Abstract

The maintenance of telomere length is required for continued cell proliferation, and ϳ85-90% 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 Vitamin D is a lipophilic hormone, and its effects are mediated by the vitamin D receptor (VDR) 1 (1), which is a member of the steroid/thyroid nuclear receptor superfamily. This superfamily includes receptors for steroids such as progesterone, androgens, estrogens, glucocorticoids and mineralocorticoids, receptors for non-steroid hormones like vitamin D, thyroid hormones, all-trans-retinoic acid, and 9-cis-retinoic acid as well as orphan receptors for which the ligand is unknown. The VDR acts as a ligand-inducible transcription factor that in most cases forms heterodimers with the retinoid X receptor (RXR). The activated receptors bind vitamin D response elements (VDREs) to regulate the expression of the target genes through activation or repression of transcription.In addition to classic effects on calcium homeostasis, bone density, and mineral metabolism, the active metabolite of vitamin D, 1,25(OH) 2 VD 3 , modulates cellular proliferation (2, 3), differentiation (4), and apoptosis (5) of both normal and malignant cells. Our recent studies have shown that the growth of multiple OCa cell lines is suppressed by 1,25(OH) 2 VD 3 (6), suggesting that active vitamin D compounds are potential therapeutic agents for OCa treatment and prevention. Molecular analyses have identified GADD45 as a primary target gene that mediates the effect of 1,25(OH) 2 VD 3 on G 2 /M arrest (7) and the p27 CDK inhibitor as the mediator for the arrest at G 1 /S checkpoint (6).The ends of chromosomes, telomeres, are subject to progressive shortening in normal somatic cells, leading ultimately to irreversible growth arrest, known as senescence (8). In contrast, the telomere length in cancer cells is stabilized by telomerase, an enzyme that catalyzes the synthesis of telomeric DNA repeats. Telomerase is a ribonucleoprotein complex containing three essential components, the telomerase RNA, which contains a sequence complementary to the telomeric TTAGGG repeat, the catalytic subunit, telomerase reverse transcriptase, which catalyzes the reverse transcription of TTAGGG repeats in the telomerase RNA, and the telomerase-associated protein 1, which helps the reverse transcription. Whereas all human somatic cells express the telomerase RNA constitutively (9, 10), the level of hTERT is increased in most human cancers, and its expression determines the cellular activity of telomerase (11). Thus, the expression of the hTERT gene appears to be the rate-limiting factor for telomerase activity in human cancer cells.The reactivation of telomerase has been shown to be one of the three events required to transform a normal human epithelial cell into a cancer cell (12). An anti-apoptotic function of telomerase has been described in human fibroblasts and neuronal cells (13)(14)(15). Studies in epid...

22‐Oxa‐1,25‐dihydroxyvitamin D3 efficiently inhibits tumor growth in inoculated mice and primary histoculutre of cholangiocarcinoma

“…39,40 In addition, vitamin D inhibits the expression of telomerase, an enzyme that adds a specific DNA sequence repeat to the 3 0 end of DNA strands, resulting in cell death. 41,42 In the current investigation, we noted that supplementation with 22-oxa-D 3 also up-regulated the expression of VDR, a receptor that is necessary for the genomic action of vitamin D. This observation is was evident in cell cultures, in the mouse model, and in the HDRA. It also has been demonstrated that the antitumor growth …”

1,25-Dihydroxyvitamin D3 Suppresses Telomerase Expression and Human Cancer Growth through MicroRNA-498

“…After ligand binding, the VDR forms a heterodimer with retinoid X receptor (RXR) and binds to vitamin D-responsive elements (VDREs) in the regulatory region of target genes to activate or repress their transcription (23). Previous studies have shown that the growth of multiple human ovarian cancers was suppressed by 1,25(OH) 2 D 3 (24,25) and that 1,25(OH) 2 D 3 -induced apoptosis involved down-regulation of telomerase activity (26). This study identifies miR-498 as a primary target gene for 1,25(OH) 2 D 3 , which binds to the 3Ј-UTR of hTERT and decreases its mRNA expression to induce cell death.…”

“…cDNA was reverse-transcribed from 1 g of total cellular RNA with random hexamer primers and thermostable reverse transcriptase (Invitrogen). Analyses of hTERT and GAPDH expression by RT-PCR were performed as described previously (26). To quantify hTERT and GAPDH expression, PCR products were subjected to electrophoresis in a 15% polyacrylamide gel.…”

“…Telomerase Assays-Telomerase activity was measured by the telomeric repeat amplification protocol assay using the telomerase PCR-enzyme-linked immunosorbent assay kit (Roche Applied Science) as described (26).…”

Recent Candidate Molecular Markers: Vitamin D Signaling and Apoptosis Specific Regulator of p53 (ASPP) in Breast Cancer

“…It has also reported that some breast cancer cells shows potentiate TNF alpha induced apoptosis through the death receptor pathway, which is linked to the activation of caspases and phospholipase A2 (Colston and Hansen, 2002). A novel mechanism of 1α 25(OH) 2 D 3 -mediated apoptosis in epithelial ovarian cancer cells was proposed by Jiang et al(2004), wherein they showed that 1 α 25(OH) 2 D 3 destabilizes telomerase reverse transcriptase (TERT) mRNA, therefore inducing apoptosis through telomere attrition resulting from the down-regulation of telomerase activity and it is first study which demonstrate stability of hTERT mRNA by a hormone. The proposed mechanism for induction of apoptosis followed by the 1α 25(OH) 2 D 3 -VDR complex induces Vitamin D3-Upregulated Protein 1 and 2, which negatively regulates thioredoxin function and expression.…”