The effects of 1,25-dihydroxyvitamin D3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling

Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH)2D3 increases cytosolic Ca2+ concentration and transiently activates RhoA and i...

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Published inJournal of steroid biochemistry and molecular biology Vol. 121; no. 1-2; pp. 355 - 361
Main Authors ORDONEZ-MORAN, Paloma, ALVAREZ-DIAZ, Silvia, VALLE, Noelia, LARRIBA, María Jesús, BONILLA, Félix, MUNOZ, Alberto
Format Conference Proceeding Journal Article
LanguageEnglish
Published Kidlington Elsevier 01.07.2010
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Abstract Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH)2D3 increases cytosolic Ca2+ 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)2D3 and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH)2D3 24-hydroxylase (CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH)2D3. Moreover, 1,25(OH)2D3 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)2D3 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)2D3 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)2D3 in colon cancer cells.
AbstractList Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts wide gene regulatory effects in human colon cancer cells. We previously reported that 1,25(OH)2D3 increases cytosolic Ca2+ 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)2D3 and disrupts the adhesive phenotype of HT29 cells. ROCK and MSK inhibition also abrogates the induction of 1,25(OH)2D3 24-hydroxylase (CYP24), E-cadherin, and vinculin and the repression of cyclin D1 by 1,25(OH)2D3. Moreover, 1,25(OH)2D3 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)2D3 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)2D3 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)2D3 in colon cancer cells.
Author LARRIBA, María Jesús
BONILLA, Félix
VALLE, Noelia
MUNOZ, Alberto
ORDONEZ-MORAN, Paloma
ALVAREZ-DIAZ, Silvia
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Issue 1-2
Keywords Cystatin
MSK
Steroid hormone
Cholecalciferol(1,25-dihydroxy)
Gene regulation
Malignant tumor
RhoA
Micronutrient
Colonic disease
Signal transduction
Colon cancer
Gene
Vitamin D
Cystatin D
Digestive diseases
Intestinal disease
Cancer
Language English
License CC BY 4.0
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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Snippet Many studies support a protective action of vitamin D against colon cancer. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts wide gene regulatory effects in...
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SubjectTerms Biological and medical sciences
Calcitriol - metabolism
Cell Line, Tumor
Cell Membrane - metabolism
Cell Proliferation
Colonic Neoplasms - metabolism
Cyclin D1 - metabolism
Cystatins - metabolism
Fundamental and applied biological sciences. Psychology
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic
Humans
Medical sciences
Membrane Proteins - metabolism
Microscopy, Confocal - methods
Occludin
p38 Mitogen-Activated Protein Kinases - metabolism
rho-Associated Kinases - metabolism
rhoA GTP-Binding Protein - metabolism
Ribosomal Protein S6 Kinases, 90-kDa - metabolism
Signal Transduction
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tight Junctions - metabolism
Tumors
Vertebrates: endocrinology
Vertebrates: reproduction
Title The effects of 1,25-dihydroxyvitamin D3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling
URI https://www.ncbi.nlm.nih.gov/pubmed/20223287
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