Study helps clarify role of vitamin D in cancer therapy

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Public release date: 17-Nov-2008

http://www.eurekalert.org/pub_releases/2008-11/rup-shc110408.php

Contact: Rita Sullivan

Rockefeller University Press

Study helps clarify role of vitamin D in cancer therapy

A colon cancer cell isn't a lost cause. Vitamin D can tame the rogue

cell by adjusting everything from its gene expression to its

cytoskeleton. In the Nov. 17 issue of the Journal of Cell Biology,

Ordóñez-Morán et al. show that one pathway governs the vitamin's diverse

effects. The results help clarify the actions of a molecule that is

undergoing clinical trials as a cancer therapy.

Vitamin D stymies colon cancer cells in two ways. It switches on genes

such as the one that encodes E-cadherin, a component of the adherens

junctions that anchor cells in epithelial layers. The vitamin also

induces effects on the cytoskeleton that are required for gene

regulation and short-circuiting the Wnt/b-catenin pathway, which is

overactive in most colon tumors. The net result is to curb division and

prod colon cancer cells to differentiate into epithelial cells that

settle down instead of spreading.

To delve into the mechanism, the team dosed colon cancer cells with

calcitriol, the metabolically active version of vitamin D. Calcitriol

triggered a surge of calcium into the cells and the subsequent switching

on of RhoA–RhoGTPases, which have been implicated in the cytoskeletal

changes induced by vitamin D. The activated RhoA in turn switched on one

of its targets, the rho-associated coiled kinase (ROCK), which then

roused two other kinases. Each step in this nongenomic pathway was

necessary to spur the genomic responses, the researchers showed. The

team also nailed down the contribution of the vitamin D receptor (VDR).

The receptor was crucial at the beginning of the pathway, where it

permitted the calcium influx, and at the end, where it activated and

repressed genes.

The study is the first to show that vitamin D's genomic and nongenomic

effects integrate to regulate cell physiology. One question the

researchers now want to pursue is whether VDR from different

locations—the nucleus, the cytosol, and possibly the cell membrane—has

different functions in the pathway.

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Ordóñez-Morán, P., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200803020.

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ne Holden, MS, RD

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