RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells.
The active vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits proliferation and promotes differentiation of colon cancer cells through the activation of vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. Additionally, 1,25(OH)(2)D(3) has several nongenomic effects of uncertain relevance. We show that 1,25(OH)(2)D(3) induces a transcription-independent Ca(2+) influx and activation of RhoA-Rho-associated coiled kinase (ROCK). This requires VDR and is followed by activation of the p38 mitogen-activated protein kinase (p38MAPK) and mitogen- and stress-activated kinase 1 (MSK1). As shown by the use of chemical inhibitors, dominant-negative mutants and small interfering RNA, RhoA-ROCK, and p38MAPK-MSK1 activation is necessary for the induction of CDH1/E-cadherin, CYP24, and other genes and of an adhesive phenotype by 1,25(OH)(2)D(3). RhoA-ROCK and MSK1 are also required for the inhibition of Wnt-beta-catenin pathway and cell proliferation. Thus, the action of 1,25(OH)(2)D(3) on colon carcinoma cells depends on the dual action of VDR as a transcription factor and a nongenomic activator of RhoA-ROCK and p38MAPK-MSK1.
Ordóñez-Morán
Paloma
P
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Larriba
María Jesús
MJ
Pálmer
Héctor G
HG
Valero
Ruth A
RA
Barbáchano
Antonio
A
Duñach
Mireia
M
de Herreros
Antonio García
AG
Villalobos
Carlos
C
Berciano
María Teresa
MT
Lafarga
Miguel
M
Muñoz
Alberto
A
D000818:Animals; D015703:Antigens, CD; D018938:Caco-2 Cells; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase; D014815:Vitamins / Q000378:metabolism* / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C577585:Fzr1 protein, mouse; D018167:Receptors, Calcitriol; D014815:Vitamins; D051153:Wnt Proteins; D051176:beta Catenin; C066737:RHOA protein, human; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002117:Calcitriol; D002118:Calcium