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Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms

Key Points

  • Colorectal cancer is one of the main causes of cancer mortality in Western societies.

  • Experimental, epidemiological and clinical evidence show that diets consumed by Western populations have an important role in the modulation of this disease.

  • Calcium, vitamin D and folate have emerged as promising chemopreventive agents in colon cancer.

  • One of the main pathways used by extracellular calcium to exert its chemopreventive actions is through activation of a calcium-sensing receptor. This results in increased levels of intracellular calcium, inducing a wide range of biological effects, some of which restrain the growth and promote the differentiation of transformed colon cells.

  • Most of the pleiotropic actions of vitamin D are mediated by binding to a nuclear receptor, which interacts with specific consensus sites in promoters of specific genes, resulting in downregulation or upregulation of their expression. The actions of vitamin D involve cross-talk with growth factors/cytokines, inhibitory effects on the cell cycle and stimulation of apoptosis.

  • Folate lies at the intersection of metabolic pathways involved in DNA methylation and biosynthesis. Three main mechanisms by which decreased levels of folate (and of other dietary one-carbon donors) might increase the risk of cancer are: alteration of the normal DNA-methylation process; imbalance of the steady-state level of DNA precursors, leading to aberrant DNA synthesis and repair; and chromosome and chromatin changes.

  • It is proposed that, together with the application of genome methodology to elucidate nutrient–gene interactions, a deliberate effort should be made to identify nutrient-induced key events in signal-transduction pathways and in the cell cycle that are involved either in the chemoprevention or promotion of colorectal cancer.

Abstract

Recent findings have indicated that dietary calcium, vitamin D and folate can modulate and inhibit colon carcinogenesis. Supporting evidence has been obtained from a wide variety of preclinical experimental studies, epidemiological findings and a few human clinical trials. Important molecular events and cellular actions of these micronutrients that contribute to their tumour-modulating effects are discussed. They include a complex series of signalling events that affect the structural and functional organization of colon cells.

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Figure 1: A signalling pathway of extracellular calcium.
Figure 2: Biosynthesis, and genomic and non-genomic actions of vitamin D.
Figure 3: Inhibitory action of vitamin D on the cell cycle.
Figure 4: Pro-apoptotic actions of vitamin D.
Figure 5: Decreased dietary folate intake and colon carcinogenesis.

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Acknowledgements

This work was supported by the Division of Cancer Prevention and Mouse Models of Human Cancers Consortium of the National Institutes of Health/National Cancer Institute, Bethesda, Maryland, USA.

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Correspondence to Sergio A. Lamprecht.

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DATABASES

Cancer.gov

colorectal cancer

LocusLink

Apc

β-catenin

BAK

BAX

BCL-2

CaR

CDX2

CREB

cyclin D1

CYP3A

Dnmt1

E-cadherin

EGFR

KIP1

K-RAS

Msh2

MTHFR

MYC

ODC

p38 MAPK

phospholipase A2

PLCβ

retinoblastoma

SERCA3

SMAD3

survivin

TGF-β1

TGF-β2

thymidylate synthase

Tp53

VDR

WAF1

Glossary

ONE-CARBON DONORS

Dietary components such as folate, methionine and choline. Folate is an important conveyor of one-carbon units at different states of oxidation, including the methyl (-CH3) group. Methionine donates the methyl group only.

WESTERN-STYLE DIET

(WD). A standard AIN-76A diet modified to have increased fat content, and decreased levels of calcium, vitamin D, folate and other one-carbon donors. These are reduced to nutrient-density levels approximating those found in Western diets.

ADENOMATOUS POLYPOSIS COLI

(APC) is a typical, 'gatekeeper' tumour-suppressor gene, mutations of which are crucial initiating events in the development of human colorectal cancer. Mice carrying a mutant Apc allele for example, a mutation in the region corresponding to codon 850 (Apc-mutant min mice) or to codon 1638 (Apc 1638N mice) are — predisposed to the development of intestinal polyps.

IONOPHORE

A compound that binds ions for transport across membranes.

VITAMIN-D RESPONSE ELEMENT

(VDRE). A short DNA sequence in a gene promoter to which the activated vitamin-D receptor binds and exerts its effects on transcription.

S-ADENOSYL METHIONINE

(SAM). SAM is a universal donor of the methyl group to DNA, histones and other bioactive molecules. After loss of the methyl group, SAM is converted to S-adenosyl homocysteine (SAH).

MICROSATELLITE INSTABILITY

Genetic instability due to a high mutation rate, mainly in short nucleotide repeats. Cancers with this phenotype are associated with defects in DNA mismatch-repair genes.

MISMATCH REPAIR

A genomic system that detects and repairs incorrectly paired nucleotides that are introduced during DNA replication.

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Lamprecht, S., Lipkin, M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3, 601–614 (2003). https://doi.org/10.1038/nrc1144

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