Title:Role of Calcium, Vitamin D, and the Extrarenal Vitamin D Hydroxylases in Carcinogenesis
Volume: 13
Issue: 1
Author(s): Julia Hobaus, Ursula Thiem, Doris M. Hummel and Eniko Kallay
Affiliation:
Keywords:
Cancer, Vitamin D, Calcium, CYP27B1, 1α-hydroxylase, CYP24A1, 24-hydroxylase, CYP27A1, CYP2R1, 25-hydroxylase,
calcium sensing receptor, CaSR, colorectal cancer, Proliferation, Methylation, Epigenetics, Splice variants, COX-2, Wnt
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.
