Vitamin D: Proteases, protease inhibitors and cancer

Abstract

The active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, 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)2D3 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)2D3 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)2D3 against colon cancer by mechanisms that are both dependent and independent of cathepsin inhibition. Transcriptomic studies suggest that 1,25(OH)2D3 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)2D3 in cancer cells.