The role of vitamin D and retinoids in controlling prostate cancer progression.

Abstract

Prostate cancer is a leading cause of cancer-related deaths in many countries. Premalignant lesions and invasive cancer occur more frequently in the prostate than in any organ other than the skin. Yet, the incidence of clinically detected prostate cancer is much lower than the histopathological incidence. The slow growth of prostate cancer and the low incidence of clinically manifest disease in some geographical locations or racial/ethnic groups suggest that prostate cancer can be controlled, perhaps by dietary factors. Vitamin D and retinoids have emerged as leading candidates both to prevent and to treat prostate cancer. Many of the activities of these compounds, established from epidemiological studies, research with cell culture and animal models, and clinical trials, are consistent with tumor suppressor effects. However, retinoids may have additional tumor enhancer properties that balance or negate anti-cancer activity. This perhaps explains the overall lack of protective effects of vitamin A compounds against prostate cancer found in epidemiological studies, and the minimal efficacy of retinoids in clinical trials to treat prostate cancer. While current efforts focus on developing strategies to use vitamin D compounds to control prostate cancer, the possibility exists that prostate cancer cells may become resistant to tumor suppressor effects of vitamin D. Analyses of experimental model systems show that prostate cancer cells become less sensitive to vitamin D through loss of receptors or signaling molecules that mediate vitamin D's actions, or through changes in metabolic enzymes that synthesize or degrade vitamin D compounds. The potential promise of exploiting vitamin D to control prostate cancer is tempered by the possibility that prostate cancer, perhaps even at early stages, may develop mechanisms to escape tumor suppressor activities of vitamin D and/or retinoids.

Genetically defined mouse models that mimic natural aspects of human prostate cancer development.

“…Since mice lacking both RXRb and RXRg are normal in terms of prostate morphology and function (Krezel et al 1996), and considering that the active RA receptor is mostly a heterodimer of one RAR and one RXR , the critical RXR in prostate biology appears to be RXRa. Moreover, to mediate multiple signaling pathways in the prostate, RXRa may also partner with other nuclear receptors, such as peroxisome proliferator-activated receptor g and vitamin D receptor, whose ligands have been shown to inhibit prostate cancer cell growth (Kubota et al 1998, Peehl & Feldman 2003. The human chromosomal region, 9q34.3, in which RXRa gene is mapped, is characterized by a high rate of recombination (Almasan et al 1994), and the incidence of loss of heterozygosity at this locus has been reported to be 20% in prostate cancer (Ruijter et al 1999).…”

Geographic variation of prostate cancer mortality rates in the United States: Implications for prostate cancer risk related to vitamin D

“…2 This finding is very interesting and important in that it may provide an explanation for a number of puzzling and inconsistent results from studies investigating the links between prostate cancer, solar UVB radiation (280 -315 nm) and vitamin D. While there is considerable observational epidemiologic and in vitro evidence that UVB and/or vitamin D reduce the risk of prostate cancer, 1,3,4 there are also a number of reports of no risk reduction with UVB and vitamin D. 1 While some of the effect reported by Tuohimaa et al 1 may be due to the negative effects of vitamin A (retinol) 5 found in fish liver oil, which is a major source of vitamin D in Norway, 1 this may not explain all of the increased risk of prostate cancer for higher values of 25(OH)-vitamin D 3 .…”

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

“…The observation that 1,25D prevents proliferation of prostate cancer cells (Peehl & Feldman 2003) has attracted considerable interest because of the possibility of using vitamin D based therapies for prostate cancer (Chen et al 2000. A deficiency of CYP27B1 enzyme activity levels was noted in prostate cancer cells compared with normal cells ) and this correlated with the inability of exogenous 25D to inhibit cellular proliferation presumably because of insufficient local 1,25D production by CYP27B1 .…”