Abstract
Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.
Highlights
Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality
In vivo studies have shown that administration of testosterone up-regulates the expression and activities of pyruvate dehydrogenase (PDH) and mitochondrial aspartate aminotransferase to increase the substrate pools for citrate synthesis, acetyl-CoA and oxaloacetate (Costello and Franklin, 1993; Qian et al, 1993). This suggests that vitamin D and androgen supplementation facilitate the reversion of the metabolic switch that occurs during prostate carcinogenesis by preventing citrate oxidation, partially restoring the normal prostatic function and shunting citrate into the cytoplasm for secretion and lipid synthesis (Figure 3)
Recent studies have shown a complex relationship between vitamin D3- and androgen-mediated signaling in the normal prostate and prostate cancer through their coordinated effect on mRNA and miRNA transcription, cell proliferation and cancer metabolism
Summary
There are many epidemiological studies that suggest high serum vitamin D levels, usually measured as serum 25(OH)-vitamin D3 (25(OH)D3) may be important in preventing various cancers, including breast, ovarian and colon cancer (Thorne and Campbell, 2008; Giovannucci, 2009). A recent study of men diagnosed with prostate cancer showed that 72% of men with recurrent disease and 68% with clinically localized disease were insufficient or deficient in serum 25(OH)D3 levels, less than 20 ng/mL (desirable levels >40 ng/mL) (Trump et al, 2010). These data suggest that the majority of men with prostate cancer have low circulating androgen and low 25(OH)D3 levels www.frontiersin.org
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