While current efforts focus on developing strategies to use vitamin D analogs to control prostate cancer, it is possible that prostate cancer cells could become resistant to the tumor suppressive effects of vitamin D. Some prostate cancer cells are already known to be resistant to growth inhibition by vitamin D. Analyses of experimental model systems reveal that prostate cancer cells become less sensitive to vitamin D through loss of vitamin D receptors, loss of signaling molecules that modulate vitamin D action, or through changes in metabolic enzymes, such as 1a-hydroxylase and 24-hydroxylase, that sensitize or degrade vitamin D compounds.51 Such changes have been found in experimental models, yet whether these alterations occur in human prostate cancer tissues in vivo, and the associated frequencies of occurrences still need to be determined. One study suggested that VDR levels were decreased in the prostate after age 60, which might be linked with increased incidence of prostate cancer with age,52 and development of vitamin D resistance during the disease progression.
In one of our current studies, we identified a prostate cancer cell subline, CWR22R-2, which displays more aggressive behavior in the tumor invasiveness than its parental CWR22R cells. This aggressive CWR22R-2 line displays reduced vitamin D anti-proliferative effects compared to CWR22R cells, which provides evidence that prostate cancer cells might develop resistance to vitamin D during disease progression. Further characterization of these two cell lines found reduced vitamin D transcrip-tional activity in CWR22R-2 cells, which might correlate with higher expression of VDR co-repressors such as SMRT and NCoR, and eventually result in reduced vitamin D responsiveness.53 More evidence from other prostate cancer cell lines with different vitamin D responses and from prostate cancer patient samples is needed to confirm our findings.
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