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

• Published in: Journal 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
• Language: English
• Published: Kidlington Elsevier 01.07.2010
• Subjects: 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; 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
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2010.02.031

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.