Date Published: June 8, 2011
Publisher: SAGE-Hindawi Access to Research
Author(s): Krishna Vanaja Donkena, Charles Y. F. Young.
Prostate cancer is the second common cancer in men worldwide. The prevention of prostate cancer remains a challenge to researchers and clinicians. Here, we review the relationship of vitamin D and sunlight to prostate cancer risk. Ultraviolet radiation of the sunlight is the main stimulator for vitamin D production in humans. Vitamin D’s antiprostate cancer activities may be involved in the actions through the pathways mediated by vitamin D metabolites, vitamin D metabolizing enzymes, vitamin D receptor (VDR), and VDR-regulated genes. Although laboratory studies including the use of animal models have shown that vitamin D has antiprostate cancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be inconclusive and an intensively studied subject. This review will provide up-to-date information regarding the recent outcomes of laboratory and epidemiology studies on the effects of vitamin D on prostate cancer prevention.
The World Health Organization (http://globocan.iarc.fr/factsheets/cancers/prostate.asp) indicates that prostate cancer is the second most frequently diagnosed cancer in men (903,000 new cases) and has about 258,000 deaths of this cancer worldwide in 2008. The highest incident rates are among the countries of Australia/New Zealand Western, Northern Europe, and Northern America, and the lowest age-matched incidence rates are those in South-central Asia. In the USA alone, the American Cancer Society (http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-key-statistics) estimated death and newly diagnosed cases of prostate cancer were 32,050 and 217,730 men, respectively, in year 2010. Moreover, in USA, the total medical expenditure for prostate cancer treatment was estimated as $1.3 billion in year 2000, which represents a 30% increase compared to that in 1994. In year 2004, 2.3 billion was estimated for prostate cancer alone . As being a prevalent cancer disease in men, current total cost for PCa prostate cancer treatments in USA would much exceed $2.3 billion.
Although the previtamin D 7-dehydrocholesterol was thought to be produced in the gut wall cells and transported to skin cells, actually skin cells can synthesize their own 7-dehydrocholesterol, which in turn is converted to a provitamin D, cholecalciferol, or vitamin D3, by isomerization upon ultraviolet B (UVB) radiation of sunlight in epidermis [12–14]. Further photoreaction of vitamin D3 by UVB absorption may generate inactive metabolites. Vitamin D3 is metabolized to calcidiol 25(OH)D3 in the liver by the mitochondrial sterol 27-hydroxylase (27-hydroxylase; (CYP27A1) and converted to a biologically active vitamin D, calcitriol/1,25-dihydroxyvitamin D3 (1,25(OH)2D3), by 1α-hydroxylase (CYP27B1) in the kidney and other tissues including the prostate [15–18]. Usually circulating 25(OH)D3 level is used to determine vitamin D nutritional status, because it is a predominant form of vitamin D in blood stream and has a much longer half life than that of 1,25(OH)2D3 (i.e., 15 days versus 15 hours) . Importantly, its serum concentrations may be correlated with total vitamin D levels from both endogenous production and dietary uptakes [20–23]. However, 25(OH)D3 is by no means a perfect marker for active vitaminD3status.For example, it is questionable whether measuring 25(OH)D3 can represent the bioavailability of vitamin D2 (ergocalciferol, a vitamin D proform derived from fungus products) versus vitamin D3. Some studies [24, 25] but not other  showed that vitamin D3 supplementation could increase 25(OH)D3 to higher levels than the use of vitamin D2. In fact, blood 25(OH)D3 levels can be affected by substrate availability through adiposity sequestration, skin pigmentation, physical activity [20, 27, 28], and the consumption of dietary factors such as genistein and folate [29–32].
Anticancer activities of vitamin D have been suggested to act mainly through its nuclear receptor or VDR. The VDR is a member of nuclear receptor super family, whose functions act as ligand-dependent transcription factor in the nucleus [54–56]. In addition, upon ligand activation, this receptor requires to form a heterodimer with the retinoid X receptor (RXR) in order to bind a specific genomic DNA sequence, that is, a VDRE to activate or repress gene expression [54–56]. RXR of the VDR heterodimer may be subjected to phosphorylation by prolonged activation of the mitogen-activated protein kinase pathway, resulting in the impairment of VDR-mediated prostate cell growth inhibition effects . Recently, a report showed that the vitamin D receptor can form a heterodimer with retinoic acid receptor gamma . Although it has been shown that androgen receptor and VDR may cross talk each other in their pathways [49, 59, 60], the two receptors probably do not have direct interactions. It has been reported that the expression of VDR can be regulated by several hormones including androgens, vitamin D, parathyroid hormone, retinoic acid, and glucocorticoids [55, 56]. However, the regulation of the basal line expression of the receptor is not well studied. Besides, the genomic gene regulation effects, through a so-called nongenomic mechanism, the same receptor activated by vitamin D in the plasma membrane may also have rapid modulation effects on cellular functions [55, 56, 61]. Both genomic and nongenomic effects of VDR have been demonstrated in prostate cells [43, 62, 63]. The question also arises if there is a separate membrane VDR. According to other investigators [64–66], protein disulfide isomerase family A, member 3 (PDIA3) has been identified as a membrane associated, 1,25(OH)2D3 binding protein/receptor that may exhibit some rapid nongenomic actions of 1,25(OH)2D3. PDIA3 with 1,25(OH)2D3 binding ability has recently been detected in several human prostate cell lines . The significance of PDIA3-mediated 1,25(OH)2D3 action in prostate cancer cells requires further studies.
Vitamin D deficiency or insufficiency has become a public health concern in large proportions of the populations in the United States and Northern European countries especially among ethnic groups with dark skin, and others such as those with physical inactive and little sun exposure. As mentioned above, sunlight exposure may increase vitamin D synthesis in the skin which has been thought to be beneficial to protect from some types of cancer, including prostate cancer. Of course, prolonged sunlight or UVB exposure without adequate skin protection can cause skin cancer. Indeed, there are many ecological and observational studies including case-control and prospective studies [94–106] showing a high degree of consistent results that sunlight exposure is inversely associated with prostate cancer risk.Geographic regions with less sunlight exposure seem to be related to an increased prostate cancer mortality [96, 97]. Studies [102, 103] also showed that patients diagnosed with prostate cancer in summer may have higher survival rates than that of patients in the winter due to seasonal UV irradiance levels. There are epidemiological studies [101, 107–109] suggesting that the ethnic groups with dark skin could be associated with high prostate cancer risk because high skin pigments may reduce the absorption of UV radiation. However, a study reported that black men did not increase their prostate cancer risk in terms of sunlight exposure when compared to white counterparts . There is epidemiological evidence that shows skin cancer patients may have reduced risk for procuring certain types of secondary cancer including prostate cancer [111–113]. However, the result of a study did not support the notion that sunlight induced skin cancer can protect against prostate cancer risk . Although there are overwhelming number of studies indicating that UVB exposure from sunlight consistently reduce risk of prostate cancer development and progression, yet not every study fully supports this idea. For instance, a population-based nested case-control study and meta-analysis  only provided a limited support for the effect of sunlight on reducing prostate cancer. Also, a study showed contradictory results that high levels of UVR exposure may be positively associated with the risk of prostate cancer mortality . Another group of investigators [117, 118] used their ecological approach to conduct a multicountry study consisting of 33 countries worldwide to evaluate the effect of residential UV exposure on cancer incidence. The study results did not prove that sunlight/UV exposure could decrease the risk of various cancers including prostate cancer. The investigators of this study emphasized the importance of the control for various confounders that might have been overlooked in other studies.
Unlike most of sunlight exposure studies, linking circulating vitamin D levels or vitamin D uptakes with the reduction of prostate cancer risk has not been very successful. Of course, there are some studies [119–122] seeming to support the notion that high levels of serum vitamin D have protection effects against prostate cancer. A US study indicated that serum 1,25 vitamin D3 was negatively associated with prostate cancer restricted to men above median age of 57 years . In a Fannish study with 13 yr followup of about 19,000 men, the authors found that low serum 25(OH)D3 concentrations were associated with high risk of earlier exposure to and more aggressive prostate cancer . In addition, there are two more recent reports [121, 122] with an 18 yr or a 44.0 month median time followup, respectively, suggesting that both circulating 25(OH)D3 and 1,25(OH)2D3 or 25(OH)D3 alone at median or higher than medium levels have lower risk for prostate cancer progression.
Since expression and functions of VDR, related vitamin D metabolic enzymes and vitamin D signal downstream genes are associated with vitamin D’s action, genetic variation such as the single nucleotide polymorphisms (SNP) in these genes may have impact on vitamin D action in cancer cells. Therefore, analysis of the correlation of these polymorphisms with cancer risk would be highly meaningful. Among more than 470 polymorphisms in the VDR gene [11, 17], there may be six polymorphisms including the Fok1, Cdx2, Bsm1, Apa1, and Taq1 SNPs, and Poly(A) microsatellite to be frequently studied in relation to risk of cancer including prostate cancer.
Although in vivo and in vitro laboratory studies provide strong evidence in supporting that vitamin D via VDR possesses antiprostate cancer activities, epidemiological studies have not shown consistent results for vitamin D’s antiprostate cancer activities. Among many epidemiological studies, especially those studies with measuring blood vitamin D levels produced the least overall supporting evidence for the antiprostate cancer activities. One drawback of this type of studies is that the designs mainly relied on one measurement of serum/plasma vitamin D metabolites without multiple measurements in an adequate follow-up time. The conclusion from these epidemiologic studies for prostate cancer as well as other cancers are also reflected in the Institute of Medicine’s 2011 report on dietary reference intakes for calcium and vitamin D  which could not make any conclusion if vitamin D has anticancer activities in humans. However, the inconsistency of outcomes of the epidemiologic studies may still provide a great deal of opportunities for further looking into and understanding very complexed vitamin D pathways for human cancer prevention. For example, some studies indicated that high level of serum vitamin D may, instead of decrease, increase risk of prostate cancer development or progression. The possible explanation seems to involve in local prostatic expression levels of the two vitamin D metabolizing enzymes, CYP27B1 and CYP24A1, as discussed above, which can be regulated by vitamin D, androgens and other dietary compounds. Potentially, overexpression of CYP24A1 could induce vitamin D resistance and promote risk for prostate cancer. Measuring serum vitamin D may not represent its levels at local tissues. Moreover, there is almost no information about the regulation and activities of these enzymes, as well as vitamin D metabolites in normal and cancerous prostate tissues under the in vivo conditions. Similarly, there is lacking of comprehensive information of in vivo VDR-mediated pathways in prostate cancer tissues. This could involve the interactions of genetic, epigenetic, and other endogenous and environmental factors at local tissue levels and will present challenges for developing more sophisticated study designs in the near future.