Mechanism of Antitumor Action in Prostate Cancer by Vitamin D

A key feature of cancer cells is their increased rate of growth relative to normal cells, and this can be attributed to increased cell proliferation, decreased cell death, or a combination of the two. 1,25-VD has been demonstrated to regulate cellular differentiation and proliferation in a number of normal and malignant cells, including prostate cancer cells, however the response to 1,25-VD in cancer cells appears to be cell type-specific. The majority of the 1,25-VD-mediated signals function through the VDR. The sensitivity and responsiveness of cells to vitamin D are therefore partly dependent on the activation of VDR. Miller et al. first demonstrated the presence of VDR in the LNCaP human prostate cancer cell line.23 VDRs have since been found in other prostate cancer cell lines, as well as in normal prostate epithelial and stromal cells grown in cul-ture.24 Several studies have demonstrated that 1,25-VD and its analogs inhibit the growth of prostate cancer cell lines as well as primary prostate cancer cells in culture.23-26 The 1,25-VD responsiveness is variable among cell lines tested, however the context of VDR and the 1,25-VD-mediated VDR transcriptional activity did not fully explain the different vitamin D anti-proliferative responses among cell lines. Our data and that of other investigators show that the cross-talk between vitamin D and androgen/AR signaling contributes to some degree of growth inhibition. The vitamin D anti-proliferation effect is greater in AR-expressing prostate cancer cells, such as LNCaP and CWR22R, than in AR-negative prostate cancer cells, such as DU145 and PC-3. Treatment with vitamin D enhances the AR expression, and inhibition of AR expression by antiandrogen-treatment, AR RNAi, or AR targeted disruption resulted in diminished vitamin D growth inhibition effects.27-29 Therefore, androgen/ AR signaling plays important roles in the anti-proliferative action of vitamin D in prostate cancer cell lines as summarized in Fig. 1.

Different mechanisms have been proposed for the inhibition of cell growth by vitamin D. The most common feature of response to 1,25-VD in cancer cells is the induction of G1/G0 cell cycle arrest, however, the 1,25-VD-induced G1/G0 arrest pathways are likely multi-factorial. In LNCaP cells, vitamin D treatment decreases retinoblastoma protein phosphoryla-tion, represses E2F transcriptional activity, slightly increases levels of cyclin-dependent kinase (CDK) inhibitor p21, and decreases CDK activity, finally resulting in G0/G1 accumulation.29,30 In other cancer models, such as U937 myelomonocytes, p21 appears to be the most highly up-regulated

Fig. 1. Illustration of vitamin D anti-tumor effects and of putative vitamin D responsive genes.

gene, yet, in head and neck squamous cell carcinoma (SCC), p21 is not increased, but p27 is up-regulated. Identification of a vitamin D response element (VDRE) in the p21 promoter regions suggested direct regulation of p21 activity by vitamin D/VDR, and the cell context is likely to be another determining factor. In addition to G1/G0 arrest, induction of apoptosis and differentiation of the prostate cancer cells may also contribute to the antiproliferative activity of vitamin D in some prostate cancer cells.31 Studies in breast cancer cells suggest that the vitamin D/VDR pathway seems to be involved in stimulating the mitochondria to release cytochrome C rather than a pathway relying on upstream caspases.32 The mechanisms by which 1,25-VD induces apoptosis remain to be further investigated.

In addition to its antiproliferative effect, 1,25-VD can inhibit prostate cancer cell invasion, adhesion, and migration through modulation of select cell surface adhesion molecules, such as integrins (alpha 4 and beta 4),33 and by inhibition of metallo-proteases (MMP-2 and MMP-9).34 These data suggest that 1,25-VD can not only inhibit the growth of the tumor cells, but can also stop tumor cell migration, penetration, and metastasis. Such data stimulated clinical trials of vitamin D as therapeutic agents for treatment of prostate cancer.35,36 In one of our most recent studies, we found that vitamin D prevents the prostate cancer cell invasion via modulation of selective proteinase activity. In our current study using the zymographic assay, we found that 1,25-VD inhibited MMP-9 activity and enhanced tissue inhibitors of metalloproteinase-1 (TIMP-1) activity, but had less of an effect on plasminogen activators and Cathepsin.37 Real-time PCR analysis demonstrated that 1,25-VD inhibited MMP-9 and induced TIMP-1 transcript expression in a time dependent manner. The vitamin D effects on the TIMP-1 promoter activity further suggested a potential cross-talk between AP-1 and vitamin D/VDR signalings, which might contribute to the suppression of TIMP-1. In contrast, the regulation of MMP-9 by vitamin D did not seem to be regulated at the transcriptional level, suggesting some post-transcriptional modifications, or RNA stability might contribute to the suppression of MMP-9 activity by vitamin D.37 From our study, we concluded that vitamin D modulates the activity of selective proteinases, such as MMP-9 and TIMP-1, to inhibit the prostate cancer cell invasion, and thus provides proof of the concept for treating advanced stage prostate cancer patients with vitamin D to stop disease progression.

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