RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells

J Cell Biol. 2008 Nov 17;183(4):697-710. doi: 10.1083/jcb.200803020.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD
  • Caco-2 Cells
  • Cadherins / genetics
  • Cadherins / metabolism
  • Calcitriol / metabolism
  • Calcitriol / pharmacology*
  • Calcium / metabolism
  • Cdh1 Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / genetics
  • Enzyme Activation / drug effects
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Transcription, Genetic / drug effects
  • Vitamin D3 24-Hydroxylase
  • Vitamins / metabolism*
  • Vitamins / pharmacology
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Cdh1 Proteins
  • Cell Cycle Proteins
  • Fzr1 protein, mouse
  • Receptors, Calcitriol
  • Vitamins
  • Wnt Proteins
  • beta Catenin
  • RHOA protein, human
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • rho-Associated Kinases
  • p38 Mitogen-Activated Protein Kinases
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • Calcitriol
  • Calcium