Role of calcium, vitamin D, and the extrarenal vitamin D hydroxylases in carcinogenesis

Abstract

Vitamin D deficiency and low calcium intake are considered risk factors for several cancers. Vitamin D, synthesized in the skin or ingested through the diet, is transformed through two hydroxylation steps to the active metabolite, 1α,25-dihydroxyvitamin D3 (1,25-D3). 25-hydroxylases in the liver are responsible for the first hydroxylation step. The ultimate activation is performed by the renal 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1), while the 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1) in the kidneys degrades the active metabolite. These two renal vitamin D hydroxylases control the endocrine serum 1,25-D3 levels, and are responsible for maintaining mineral homeostasis. In addition, the active vitamin D hormone 1,25-D3 regulates cellular proliferation, differentiation, and apoptosis in multiple tissues in a paracrine/autocrine manner. Interestingly, it is the low serum level of the precursor 25- hydroxyvitamin D3 (25-D3) that predisposes to numerous cancers and other chronic diseases, and not the serum concentration of the active vitamin D hormone. The extra-renal autocrine/paracrine vitamin D system is able to synthesize and degrade locally the active 1,25- D3 necessary to maintain normal cell growth and to counteract mitogenic stimuli. Thus, vitamin D hydroxylases play a prominent role in this process. The present review describes the role of the vitamin D hydroxylases in cancer pathogenesis and the cross-talk between the extra-renal autocrine/paracrine vitamin D system and calcium in cancer prevention.

Fig. (1). Crosstalk between Vitamin D and Calcium

Classical action of 1,25-dihydroxyvitamin D₃ (1,25-D₃) is mediated by binding of the vitamin D receptor (VDR) – retinoid X receptor (RXR) – 1,25-D₃ complex to Vitamin D Response Elements in the DNA. 1,25-D₃ decreases proliferation by reducing Prostaglandin E2 (PGE2) levels through inhibiting the synthesizing enzyme cyclooxygenase-2 (COX2) and inducing the degrading enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). Further 1,25-D₃ is able to increase intestinal Ca²⁺ uptake through activation of calcium channels. 1,25-D₃ counteracts Wnt signaling through increased E-cadherin and Wnt inhibitor (e.g. Dickkopf 1 and 4) expression, as well as through sequestring β-catenin in thecytoplasm. Wnt signaling can also be inhibited through calcium sensing receptor (CaSR) activation. The CaSR mediates inhibition of the Wnt pathway by reducing TCF4 expression, enhancing Wnt antagonist expression (Wnt5a, Dickkopf 5) as well as increasing β-catenin phosphorylation/ubiquitinilation. Calcium in the gut lumen is able to form complexes with irritable bile acids (e.g. lithocholic acid (LC)) which are thereby neutralized. This will counteract VDR-LC induced CYP24A1 gene expression. Phospholipids (PL), Phospholipase A (PLA), Arachidonic Acid (AA), Calcium²⁺ (Ca).