Effects of 1α,25-Dihydroxyvitamin D₃ in Human Colon Cancer Cells

Abstract

Colorectal cancer is a major health problem worldwide. Epidemiological studies and work on experimental animals strongly suggest a protective effect of 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) against colon neoplasia. 1,25(OH)₂D₃ is a pleiotropic hormone that has multiple actions in the organism. By binding to the widely expressed high affinity vitamin D receptor (VDR) it regulates the transcription rate of many genes. Other non-genomic effects of 1,25(OH)₂D₃ also appear to modulate the physiology of numerous cell types. Human normal and cancer colon epithelial cells express VDR and the key enzymes involved in 1,25(OH)₂D₃ synthesis and degradation and are, thus, responsive to the hormone. 1,25(OH)₂D₃ inhibits proliferation, induces differentiation and sometimes the apoptosis of human colon cancer cells. A great variety of mechanisms and signaling pathways are involved. Since VDR mediates most, if not all, 1,25(OH)₂D₃ actions, the control of VDR expression is a crucial aspect of 1,25(OH)₂D₃ biology. Here, the molecular mechanisms underlying the actions of 1,25(OH)₂D₃ are reviewed and the repression of the VDR gene by the transcription factor SNAIL in human colon cancer cells is discussed. Understanding these mechanisms may provide the basis for the potential use of this hormone and its non-hypercalcemic derivatives in the prevention and treatment of colon cancer.