The effects of 1,25-dihydroxyvitamin D 3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling

Many studies support a protective action of vitamin D against colon cancer. 1α,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH) 2D 3 increases cytosolic Ca 2+ concentration and transiently activates RhoA and...

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Published inThe Journal of steroid biochemistry and molecular biology Vol. 121; no. 1; pp. 355 - 361
Main Authors Ordóñez-Morán, Paloma, Álvarez-Díaz, Silvia, Valle, Noelia, Larriba, María Jesús, Bonilla, Félix, Muñoz, Alberto
Format Journal Article
LanguageEnglish
Published Elsevier Ltd 01.07.2010
Subjects
Colon cancer
Cystatin D
Gene regulation
MSK
RhoA
Vitamin D
ROCK
1,25(OH) 2D 3
Colon cancer
MSK
Vitamin D
VDR
Gene regulation
Cystatin D
MAPK
RhoA
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Abstract Many studies support a protective action of vitamin D against colon cancer. 1α,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH) 2D 3 increases cytosolic Ca 2+ concentration and transiently activates RhoA and its effector the Rho-associated coiled-kinase (ROCK), and later p38MAPK-MSK. We found that the inhibition of ROCK signaling by Y27632 or that of MSK by Ro318220 prevent the formation of epithelioid islands of SW480-ADH cells by 1,25(OH) 2D 3 and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH) 2D 3 24-hydroxylase ( CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH) 2D 3. Moreover, 1,25(OH) 2D 3 does not promote the localization of the tight junction protein occludin at the plasma membrane in cells expressing a dominant negative RhoA (N19-RhoA). In addition, 1,25(OH) 2D 3 specifically increases the level of the cysteine protease-inhibitor cystatin D, whereas that of cystatin SN is unaffected. The increase of cystatin D protein caused by 1,25(OH) 2D 3 is abrogated in N19-RhoA cells. Thus, activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH) 2D 3 in colon cancer cells.
AbstractList Many studies support a protective action of vitamin D against colon cancer. 1α,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH) 2D 3 increases cytosolic Ca 2+ concentration and transiently activates RhoA and its effector the Rho-associated coiled-kinase (ROCK), and later p38MAPK-MSK. We found that the inhibition of ROCK signaling by Y27632 or that of MSK by Ro318220 prevent the formation of epithelioid islands of SW480-ADH cells by 1,25(OH) 2D 3 and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH) 2D 3 24-hydroxylase ( CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH) 2D 3. Moreover, 1,25(OH) 2D 3 does not promote the localization of the tight junction protein occludin at the plasma membrane in cells expressing a dominant negative RhoA (N19-RhoA). In addition, 1,25(OH) 2D 3 specifically increases the level of the cysteine protease-inhibitor cystatin D, whereas that of cystatin SN is unaffected. The increase of cystatin D protein caused by 1,25(OH) 2D 3 is abrogated in N19-RhoA cells. Thus, activation of the RhoA-ROCK-p38MAPK-MSK signaling pathway is essential for the regulation of the phenotype and of the CST5/cystatin D candidate tumor suppressor and other target genes by 1,25(OH) 2D 3 in colon cancer cells.
Author Álvarez-Díaz, Silvia
Ordóñez-Morán, Paloma
Bonilla, Félix
Muñoz, Alberto
Valle, Noelia
Larriba, María Jesús
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Keywords ROCK
1,25(OH) 2D 3
Colon cancer
MSK
Vitamin D
VDR
Gene regulation
Cystatin D
MAPK
RhoA
Language English
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Snippet Many studies support a protective action of vitamin D against colon cancer. 1α,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3) exerts wide gene regulatory effects in...
SourceID elsevier
SourceType Publisher
StartPage 355
SubjectTerms Colon cancer
Cystatin D
Gene regulation
MSK
RhoA
Vitamin D
Title The effects of 1,25-dihydroxyvitamin D 3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling
URI https://dx.doi.org/10.1016/j.jsbmb.2010.02.031
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