Fig. 1

Synthesis, metabolism and anticancer mechanism of vitamin D. Sunlight, specifically ultraviolet-B radiation, converts 7-dehydrocholesterol (7-DHC) into vitamin D₃ in the skin. Vitamin D₃ then enters the blood stream as complexes with vitamin D binding protein (DBP) and albumin. Liver mitochondrial and microsomal 25-hydroxylases (25-OHases), encoded by the gene CYP27A1, carry out the first hydroxylation of vitamin D to form 25(OH)D₃. 25(OH)D₃ is then 1a-hydroxylated by mitochondrial 1a-hydroxylase (1a-OHase) encoded by the CYP27B1 gene to form 1a,25(OH)₂D₃ in the kidneys and other tissues. The vitamin D receptor (VDR) is a member of the nuclear receptor family that regulates gene transcription by forming a hetero-dimer with RXR, which binds to vitamin D-response elements (VDRE) in the promoter regions of target genes. Several 1,25(OH)₂D₃ target genes have been reported multiple molecular pathways of anti-tumor actions of 1,25(OH)₂D₃ in ovarian cancer. These include (1) the up-regulation of cyclin-dependent kinase(CDK) inhibitors P21 and P27 and the subsequent inhibition of G₁/S checkpoint; (2) G₂/M arrest by 1,25(OH)₂D₃ through the induction of GADD45; (3) the inhibition of tumor angiogenesis due to suppressive effects on the expression of HIF-1/VEGFR pathway; (4) the suppression of invasion and metastasis via the up-regulation of E-cadherin and the down-regulation of β-catenin; (5) the induction of cell apoptosis by the suppression of hTERT mRNA transcription which miR-498 was a primary target gene of 1,25(OH)₂D₃; (6) the down-regulation of the expression of COX-1 and COX-2 to inhibit the inflammatory process; (7) 1,25(OH)2D3 can induce a slow increase of Ca²⁺ that activates CaMKK-β, a Ca²⁺-activated kinase that was identified as a direct activator of AMPK. DNA-damage-inducible transcript 4 (DDIT4) played a critical role in the cellular response to cell metabolism by the mTOR pathway