Abstract
BackgroundClinical trials have been conducted to clarify the beneficial effects of VD3 (1α,25-dihydroxy vitamin D3, also known as calcitriol) treatment in prostate cancer. However, the molecular mechanisms underlying these effects are not fully understood. Recent studies on IGFBP-3 have indicated its intracellular functions in cell growth and apoptosis. The aim of this study was to confirm the benefits of low-dose VD3 treatment and clarify the molecular mechanisms underlying these beneficial effects in prostate cancer cells.MethodsThe molecular effects of simultaneous treatment of LNCaP cells and their genetically modified cell lines with low concentration of docetaxel and VD3 were biologically and biochemically analyzed. To further determine the effects of VD3 treatment on IGFBP-3 induction system, cells were temporarily treated with VD3 in combination with a transcriptional inhibitor or protein synthesis inhibitor. Bcl-2 protein and its mRNA behavior were also observed in Igfbp-3 expression-modified LNCaP cells to determine the involvement of IGFBP-3 in the suppression of Bcl-2 by VD3 treatment.ResultsChanges in IGFBP-3 expression levels in LNCaP cells indicated that it mediated the inhibition of cell growth induced by VD3 treatment. IGFBP-3 was also found to be a mediator of the enhanced cytotoxicity of prostate cancer cells to VD3 in combination with the anti-cancer drug. We further identified the distinct property of the IGFBP-3 induction system, wherein temporal VD3 stimulation-induced prolonged IGFBP-3 expression and VD3 treatment-induced increase in IGFBP-3 expression were optimized based on the protein concentration rather than the mRNA concentration. Meanwhile, Bcl-2 expression was down-regulated by VD3 treatment in an IGFBP-3-independent manner.ConclusionThese findings indicate the molecular mechanisms of IGFBP-3 induction stimulated by VD3 and IGFBP-3 independent Bcl-2 suppression by VD3 treatment in prostate cancer cells. The results could prompt a re-evaluation of VD3 usage in therapy for patients with prostate cancer.
Highlights
Clinical trials have been conducted to clarify the beneficial effects of VD3 (1α,25-dihydroxy vitamin D3, known as calcitriol) treatment in prostate cancer
The purpose of our study was to investigate the role of VD3-Insulinlike growth factor binding protein-3 (IGFBP-3) induction system in cell growth inhibition and to propose the potency of low-dose VD3 usage which could evade side-effect of VD3 treatment such as hypercalcemia in therapy for patients with prostate cancer, 1 nM of DHT and 10 nM of VD3 concentrations were chosen as minimum but stably working concentration for following experiment
It has been demonstrated that simultaneous treatment with VD3 and DHT enhanced the reduction of cell growth rate compared to treatment with VD3 alone, and a similar result was reproduced with low-dose DHT (1 nM) and VD3 (10 nM) in this study (Fig. 1a, right)
Summary
Clinical trials have been conducted to clarify the beneficial effects of VD3 (1α,25-dihydroxy vitamin D3, known as calcitriol) treatment in prostate cancer. The aim of this study was to confirm the benefits of low-dose VD3 treatment and clarify the molecular mechanisms underlying these beneficial effects in prostate cancer cells. Recent epidemiological investigations have reported that higher vitamin D concentration could prevent multiple types of tumorigenesis [9]. Consistent with such finding, for example, an increase in colon cancer incidence with lower vitamin D dietary habits has been reported [10, 11]. Patients with prostate cancer need a less burdensome treatment in order to avoid potential harm from excessive treatment
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