Vitamin D and systemic cancer: is this relevant to malignant melanoma?

Abstract

1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin ...

A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma

“…This is reported to have greater transactivation potential than the short protein, translated at the conventional start codon in exon 2 (VDRA) (Gardiner and Eisman, 2003), although this has not been consistently reported (Sunn et al, 2001). The majority of evidence is that vitamin D and the VDR have a protective effect in cancer (Osborne and Hutchinson, 2002). Therefore, if A-1012G were determining the transcription start site, then the G allele would be expected to be associated with the VDRB1 protein and the A allele with the shorter VDRA protein, which would be further altered by the f allele of the Fok 1 polymorphism.…”

Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

“…various growth factors and Bcl-2). 20 In this context, it is interesting that p53, an activator of the apoptotic cascade, can suppress basal as well as IR-induced sCLU expression in both MCF-7 (breast cancer) and HCT116 (colon cancer) cells by repressing CLU promoter activity and transcription. 17 Recent clinical results by our group appear to support this theory in vivo (Willis and Boothman et al, unpublished data), in which loss of functional p53 appears to result in lost nCLU function.…”

“…1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) or its analogues inhibit proliferation and induce apoptosis in a broad variety of cell lines, including cancer cells. 13,20,[30][31][32] Other factors that have been shown to affect the expression of CLU in tumour cells include various growth factors that mediate proliferation and differentiation signals that are important for tumour cell growth. CLU mRNA was induced and activated in PC12 prostate cancer cells by nerve growth factor and epidermal growth factor.…”

Vitamin D receptor polymorphisms: no association with type 1 diabetes in the Finnish population

“…Vitamin D is also a potent regulator of cell growth and differentiation and thus a candidate for cancer regulation. In addition, some cancer cells express vitamin D receptor molecules and a number of studies indicate that vitamin D or its analogues can inhibit cancer proliferation (9,10). It has been demonstrated in experimental studies that vitamin D prevents or markedly suppresses the development of various autoimmune diseases in animal models.…”