Vitamin D: Proteases, protease inhibitors and cancer

Abstract

The active vitamin D metabolite 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), Calcitriol) is a major regulator of gene expression in higher organisms. Protein abundance is an endpoint of gene expression that results from the balance between induction and degradation and is essential for adequate cell function. Proteins are degraded by proteases whose activity is in turn controlled by a number of endogenous protease inhibitors. 1,25(OH)(2)D(3) regulates several proteases and protease inhibitors in different cell types, putatively contributing to its regulatory effects of cell physiology. We have recently shown that 1,25(OH)(2)D(3) strongly induces the expression of cystatin D, an inhibitor of several cysteine proteases of the cathepsin family. Cystatin D induction may contribute to the antitumor effect of 1,25(OH)(2)D(3) against colon cancer by mechanisms that are both dependent and independent of cathepsin inhibition. Transcriptomic studies suggest that 1,25(OH)(2)D(3) also modulates the function of the ubiquitin-proteasome system. Thus, proteases and protease inhibitors are candidates to mediate to a certain extent the complex action of 1,25(OH)(2)D(3) in cancer cells.

Dual role of hematopoietic progenitor kinase 1 (HPK1) as a positive regulator of 1α,25-dihydroxyvitamin D-induced differentiation and cell cycle arrest of AML cells and as a mediator of vitamin D resistance

“…36 This indicates that the previously documented non-apoptotic functions of caspases 37 may contribute to the effects of QVD on AML cells, similar to the antitumor effects of other protease inhibitors. 38 Consistent with the increased differentiation, G 1 arrest (G 1 /S ratio) also increases when QVD is used to inhibit HPK1 cleavage in DCS-treated 40AF cells (data not shown). A comparison of the abundance of the C-terminal cleaved fragment of HPK1 is principally expressed in hematopoietic cells 32 and is known to regulate stress responses, apoptosis and cell proliferation in cancer cells, 40 though in contrast to the current report, most previous studies focused on lymphoid cells.…”

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

“…Calcitriol modulates transcriptional, post-transcriptional, and post-translational mechanisms in a number of cell types (i.e., pre-mRNA splicing, epigenetic regulation, and protein degradation) [8,9,10]. Calcitriol has also been shown to modulate the transcription by interacting with either the positive or negative VD response element (VDRE) of the promoters of target genes [11].…”

“…Seuter et al (2013) have demonstrated that calcitriol-induced transcription correlated with the chromatin accessibility of VDR binding regions, and also that calcitriol epigenetically regulated tumor-related VDR target genes through DNA methylation and histone modifications [16,17]. Moreover, calcitriol has been shown to regulate protein degradation through the modulation of proteases and protease inhibitors [10] and specific microRNA (miRNA) processing by enhancing the expression of Dicer in cancer cells [18]. …”

Vitamin D has wide regulatory effects on histone demethylase genes

“…18,19 Moreover, 1,25(OH) 2 D 3 regulates genes that seem to lack VDR binding sites 15 and exerts posttranslational gene regulatory effects by controlling the expression of multiple proteases and protease inhibitors. 20 In addition, in certain systems, VDR has been found to interact with other transcription regulators, such as β-catenin and FoxO factors having ligand-dependent or -independent effects.…”