Different studies have described several mechanisms through which VDR can inhibit tumor growth including genomic and non-genomic signal transduction pathways. 1,25(OH)
2D
3 binds to vitamin D receptor (VDR), translocates to nucleus, where it forms a VDR/retinoid X receptor complex that binds to vitamin D response elements (VDREs) that regulate gene transcription (illustrated in Fig.
1). In addition, vitamin D exerts some non-genomic effects including regulation of calcium and phosphate homeostasis pathways, as well as activating protein kinase C, protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) and phospholipase C (PLC) [
8,
36].
The VDR variant may also be involved in ovarian cancer carcinogenesis. For example, the FokI f allele resulted in three amino acids longer VDR protein than the F allele. This mutant VDR protein was less responsive to 1,25(OH)
2D
3 and had lower transcriptional activity [
37,
38]. Etten et al. reported that this extended VDR results in lower NF-kB transcriptional activation, leading to reduced IL-12 expression and a weaker immune response [
39].
Cell cycle and apoptosis
Expression of VDR is an important factor in tumor cell response to 1,25(OH)
2D
3, which is known to influence gene expression of p53, Ras, MAPK, PI3, MYC, HIF1a, BRCA1, CDKN1A and GADD45 [
8,
12,
40‐
43]. Jiang et al. have shown that 1,25(OH)
2D
3 could inhibit cancer growth by arresting cells at the G
2–M transition phase and induce cell death through VDR-mediated, p53-independent induction of GADD45 in ovarian cancer cells [
44]. They also demonstrated that the 1,25(OH)
2D
3 analogue EB1089 inhibited the proliferation of ovarian cancer without inducing hypercalcemia in vivo [
45]. VDR-mediated induction of BRCA1 was found to be closely correlated with the anti-proliferative activity of 1,25(OH)
2D
3 in breast and prostate cancer cells [
40]. Studies have also shown that profound crosstalk exists between p53 and VDR, with the VDR gene being a direct target of p53 and its family members [
41].
1,25(OH)
2D
3 promotes the expression of cyclin-dependent kinase(CDK) inhibitors P21 and P27 with reduced CDK activity. Li et al. demonstrated that 1,25(OH)
2D
3 arrested ovarian cancer cells at the G
1/S checkpoint and stabilized the p27 protein through downregulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase [
46]. Bai et al. identified that 1,25(OH)
2D
3 suppressed ovarian cancer cells at the G
1/S checkpoint through downregulation of epidermal growth factor receptor (EGFR) transcription [
47]. Collectively, these studies confirmed that vitamin D suppressed cell proliferation through inhibitory effects on several regulators of the cell cycle.
Down-regulation of telomerase activity by vitamin D that induce apoptosis and suppress ovarian cancer cell growth may occur via other pathways [
48]. Studies by Kasiappan et al. showed that 1,25(OH)
2D
3 decreased hTERT mRNA transcription to induce cell apoptosis, suggesting that miR-498 was a primary target gene of 1,25(OH)
2D
3 for ovarian cancer [
49]. Microarray analysis has also revealed that 1,25(OH)
2D
3 regulated the extrinsic apoptotic pathway through tumor necrosis factor such as TRAIL, Fas and caspase-7 in ovarian cancer cells [
50].
Angiogenesis
Growing evidence indicates that vitamin D has a potential role for inhibiting tumor angiogenesis [
51‐
54]. Hypoxic regions exist in most solid tumors is a major pathophysiologic condition that regulates angiogenesis. Increased angiogenesis occurs as a cellular adaptation to hypoxia, which is controlled by hypoxia inducible factor-1(HIF-1). HIF1 target genes, such as vascular endothelial growth factor (VEGFR), are inhibited by 1,25(OH)
2D
3, and this molecular inhibition is mediated via a HIF-dependent pathway [
55]. A study by Chung et al. has shown that vitamin D decreased growth inhibition of tumor-derived endothelial cells from VDR knockout mice. Moreover, loss of VDR resulted in an increase in HIF-1α, VEGF, angiopoietin 1 and platelet-derived growth factor levels [
56].
Tumor metastasis is the primary factor for treatment failure in patients with ovarian cancer. The omentum is the most common tissue type affected by ovarian cancer metastasis, because it is comprised of large numbers of adipocytes, immune cells, microvascular cells and fibroblasts, which create a good microenviroment for cancer cell growth. In vivo and vitro experiments suggested that 1,25(OH)
2D
3 and its analog EB1089 could suppress the spread of cancer cells through the omentum by binding to VDR present in epithelial cancer and stromal cells [
57]. Moreover, Liu et al. found that 1,25(OH)
2D
3 upregulated the expression of E-cadherin and VDR and downregulated the expression of β-catenin in ovarian cancer induced by 7,12-dimethylbenz[a]anthracene (DMBA) [
58].
Inflammatory response
Increased inflammation has been recognized as a risk factor for the development of cancer [
59]. Mantovani et al. proposed that a continuous inflammatory environment would result in reduced levels of 25(OH)D, which may provide an explanation why cancer is associated with low levels of 25(OH)D [
60,
61]. The two isoenzymes cyclooxygenase 1 and 2 (COX-1 and COX-2) are involved in inflammatory process arrised in ovarian cancer. High-expression levels of COX-2 was associated with poor survival rates in ovarian cancer patients [
62]. Vitamin D combined with the COX-2 inhibitor celecoxib was shown to obviously decrease ovarian cancer growth rates when compared to celecoxib alone [
63].
Dysregulated tumor cell metabolism has recently been identified to play an important role in the development of cancer. Several studies have shown that vitamin D influences regulation of glucose and fatty acid metabolism in cancer cells. Santos et al. have reported that 1,25(OH)
2D
3 inhibited the expression of glycolytic enzymes including hexokinase II (HKII) and lactate dehydrogenase A (LDHA) in breast cancer [
64]. Tomasz et al. described that 1,25(OH)
2D
3 also inhibited de novo fatty acid synthesis through down-regulation of pyruvate carboxylase, while acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) were not altered in breast cancer cell [
65]. 1,25(OH)
2D
3 has also been shown to decrease the expression of genes regulating glucose, fatty acid and glutamine metabolism in prostate cancer cells [
66]. Moreover, glutamine metabolism in breast cancer was also decreased by 1,25(OH)
2D
3 intervention [
67]. However, no studies were found about the impact of 1,25(OH)
2D
3 on ovarian cancer cell metabolism.
Recent studies have demonstrated the effects of 1,25(OH)
2D
3 on metabolism-related signaling molecules, including AMPK, DDIT4, mTOR and AKT [
68‐
71]. 1,25(OH)
2D
3 can induce a slow increase in Ca
2+ concentration that activates CaMKK-β, which is a Ca
2+-activated kinase that was identified as a direct activator of AMPK [
72]. DNA-damage-inducible transcript 4 (DDIT4), also known as REDD1/Dig2/RTP801, was over-expressed in high-grade ovarian cancer and significantly linked with late stage cancer patients [
73]. DDIT4 played a critical role in cellular response to energy stress via the TSC/mTOR pathway [
74]. It has been reported that 1,25(OH)
2D
3 regulates mTOR signaling through inducing DDIT4 expression [
75]. In addition, study found that AKT S473 activation was associated with over-expression of DDIT4 in ovarian cancer tissues [
73]. These observations implied that the action of 1,25(OH)
2D
3 on the mTOR signal pathway may have a key role in cancer metabolism. Therefore, it is clear that further understanding of the pathway relating vitamin D to cancer cell metabolism is required.
Obesity has been proposed to lead to low body vitamin D status, because vitamin D is a fat soluble molecule that can be stored in excess adipose tissue [
76]. Strong links between vitamin D and obesity have been further established [
77]. It was reported that vitamin D deficiency was associated with an increased risk of ovarian cancer in overweight and obese women [
78,
79]. Obesity has been a significant risk factor for ovarian cancer [
80]. It was meaningful to elucidate the regulatory mechanisms of vitamin D in the metabolic pathway between obesity and cancer. Leptin is an adipocyte-derived adipokine that plays a crucial role in regulating appetite and energy balance, that is strongly elevated in obese ovarian cancer patients [
81]. Bai et al. reported evidence that 1,25(OH)
2D
3 had a suppressive effect on leptin and HFD-induced ovarian cancer through miR498 pathway [
82]. This means that appropriate control of 1,25(OH)
2D
3 levels may offer an effective strategy for reducing ovarian cancer risk in obese women.