Vitamin D, Wnt, Snail and colon cancer
Prof. Alberto Muñoz, Instituto de Investigaciones Biomédicas, CSIC-UAM, Madrid, Spain.
Many epidemiological and preclinical data suggest a protective and perhaps therapeutic effect of
vitamin D against colon cancer. Calcitriol (1,25-dihydroxyvitamin D3 or 1,25(OH)2D3), the
most active vitamin D metabolite, is a pleiotropic hormone with major gene expression
regulatory activity in higher organisms.
Our results show 1,25(OH)2D3 inhibits proliferation and promotes differentiation of human
colon cancer cells. 1,25(OH)2D3 induces CDH1/E-cadherin gene transcription and it antagonizes
the Wnt/-catenin signalling pathway, which is aberrantly activated in most human colon
cancers, by at least three mechanisms: a) promoting vitamin D receptor (VDR) binding to catenin, thus reducing the formation of -catenin/TCF4 complexes and their transcriptional
activity, b) inducing the nuclear export of -catenin, and c) inducing the expression of
DICKKOPF (DKK)-1, a Wnt inhibitor (1,2).
1,25(OH)2D3 regulates numerous genes in human colon cancer cells that code for proteins with a
wide range of biological activities (3). Our data show that this activity requires the activation of
a rapid non-genomic signalling pathway that includes the entry of Ca2+ from the external
medium and the posterior activation of the RhoA GTPase and the kinases ROCK, p38MAPK
and MSK. This pathway is also necessary for the antagonism of Wnt/-catenin signalling and
the inhibition of cell proliferation (4).
1,25(OH)2D3 induces CST5 gene encoding the protease inhibitor Cystatin D, which behaves as a
candidate tumour suppressor gene (5), and represses SPROUTY (SPRY)-2, which regulates
signalling from tyrosine kinase receptors and behaves as an oncogene in colon cancer (6). The
regulation of CDH1/E-cadherin, DKK-1, CST5/cystatin D and SPRY-2 must contribute to the
protective action of 1,25(OH)2D3 against colorectal cancer.
We have shown that the transcription factors Snail1 and Snail2, known as inducers of epithelialto-mesenchymal transition, repress VDR expression and block 1,25(OH)2D3 action in colon
cancer cells. Snail1 and Snail2 expression is upregulated in human colorectal tumours and
inversely correlates with that of VDR. Our data suggest that high levels of Snail1 and Snail2 are
probably responsible for VDR downregulation in colon cancer and may generate resistance to
treatments with 1,25(OH)2D3 or its analogs (7,8).
Recently, we have identified novel nuclear proteins regulated by 1,25(OH)2D3 in colon cancer
cells by means of comparative proteomic studies. Remarkably, several regulated proteins belong
to the splicesome, suggesting that the splicing process that is frequently altered in cancer may be
controlled by 1,25(OH)2D3 (9).
Pálmer et al., J. Cell Biol., 2001.:
Héctor G. Pálmer, José Manuel González-Sancho, Jesús Espada, María T. Berciano, Isabel Puig, Josep Baulida,
Miguel Quintanilla, Amparo Cano, Antonio García de Herreros, Miguel Lafarga, and Alberto Muñoz. "Vitamin D3
promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of ß-catenin
signaling". Journal of Cell Biology, 154, 369-388 (2001).
Aguilera et al., Carcinogenesis, 2007:
Óscar Aguilera, Cristina Peña, José Miguel García, María Jesús Larriba, Paloma Ordóñez-Morán, Diego Navarro,
Antonio Barbáchano, Isabel López de Silanes, Esteban Ballestar, Mario F. Fraga, Manel Esteller, Carlos Gamallo,
Félix Bonilla, José Manuel González-Sancho and Alberto Muñoz
The Wnt antagonist DICKKOPF-1 gene is induced by 1,25-dihydroxyvitamin D3 associated to the differentiation
of human colon cancer cells“. Carcinogenesis, 28, 1877-1884 (2007).
Pálmer et al., Cancer Res., 2003:
Héctor G. Pálmer, Marta Sánchez-Carbayo, Paloma Ordóñez-Morán, María Jesús Larriba, Carlos Cordón-Cardó and
Alberto Muñoz. “Genetic signatures of differentiation induced by 1,25 dihydroxyvitamin D3 in human colon
cancer cells”. Cancer Research, 63, 7799-7806 (2003).
Ordóñez-Morán et al., J. Cell Biol., 2008:
Paloma Ordóñez-Morán, María Jesús Larriba, Héctor G. Pálmer, Ruth A. Valero, Antonio Barbáchano, Mireia
Duñach, Antonio García de Herreros, Carlos Villalobos, María Teresa Berciano, Miguel Lafarga and Alberto
Muñoz. “RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype and Wnt
pathway in colon cancer cells”. Journal of Cell Biology, 183, 697-710 (2008).
Álvarez-Díaz et al., J. Clin. Invest., 2009:
Silvia Álvarez-Díaz, Noelia Valle, José Miguel García, Cristina Peña, José María Pérez-Freije, Víctor Quesada,
Aurora Astudillo, Félix Bonilla, Carlos López-Otín and Alberto Muñoz. “Cystatin D is a candidate tumor suppressor
gene induced by vitamin D in colon cancer cells”. Journal of Clinical Investigation, 119, 2343-2358 (2009).
Barbáchano et al., Oncogene, 2010:
Antonio Barbáchano, Paloma Ordóñez-Morán, José Miguel García, Agustín Sánchez, Fábio Pereira, María Jesús
Larriba, Natalia Martínez, Javier Hernández, Stefania Landolfi, Félix Bonilla, Héctor G. Pálmer, José María Rojas,
and Alberto Muñoz. “SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell
tumourigenicity”. Oncogene, 29, 4800-4813 (2010).
Pálmer et al., Nature Medicine, 2004:
Héctor G. Pálmer, María Jesús Larriba, José Miguel García, Paloma Ordóñez-Morán, Cristina Peña, Sandra Peiró,
Isabel Puig, Rufo Rodríguez, Ricardo de la Fuente, Antonio Bernad, Marina Pollán, Félix Bonilla, Carlos Gamallo,
Antonio García de Herreros and Alberto Muñoz. “The transcription factor SNAIL represses vitamin D receptor
expression and responsiveness in human colon cancer”. Nature Medicine, 10, 917-919 (2004).
Larriba et al., Carcinogenesis, 2009:
María Jesús Larriba, Ester Martín-Villar, José Miguel García, Fabio Pereira, Cristina Peña, Antonio García de
Herreros, Félix Bonilla, and Alberto Muñoz. “Snail2 cooperates with Snail1 in the repression of vitamin D receptor
in colon cancer”. Carcinogenesis, 30, 1459-1468 (2009).
Cristobo et al., submitted.
Iván Cristobo, María Jesús Larriba, Vivian de los Ríos, Francisco García, Alberto Muñoz and J. Ignacio Casal.
1α,25-Dihydroxyvitamin D3 regulates the splicesome proteome of human colon cancer cells.
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