HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

Biochem Biophys Res Commun. 2014 Mar 28;446(1):68-72. doi: 10.1016/j.bbrc.2014.02.078. Epub 2014 Feb 25.

Abstract

Background: Simvastatin is widely used to lower cholesterol levels in patients with cardiovascular diseases, although accumulating evidence suggests that statins, such as simvastatin, also exert numerous anti-tumoral effects.

Aim: The aim of this study was to examine the effect of simvastatin on colon cancer cell migration.

Methods: Migration assays were performed to evaluate CCL17-induced colon cancer cell (HT-29) chemotaxis. In vitro tumor growth and apoptosis were assessed using a proliferation assay and annexin V assay, respectively. Active RhoA protein levels in CCL17-stimulated colon cancer cells were quantified using a G-LISA assay.

Results: We found that simvastatin dose-dependently decreased CCL17-induced colon cancer cell migration. Simvastatin had no effect on colon cancer cell proliferation or apoptosis. Inhibition of beta chemokine receptor 4, CCR4, reduced CCL17-evoked activation of RhoA in colon cancer cells. Moreover, administration of mevalonate reversed the inhibitory effect of simvastatin on CCL17-induced colon cancer cell migration. Interestingly, co-incubation with geranylgeranyl pyrophosphate (GGPP) antagonized the inhibitory impact of simvastatin on colon cancer cell migration triggered by CCL17. Moreover, we observed that simvastatin decreased CCL17-induced activation of RhoA in colon cancer cells. Administration of mevalonate and GGPP reversed the inhibitory effect of simvastatin on CCL17-provoked RhoA activation in colon cancer cells.

Conclusions: Taken together, our findings show for the first time that HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via inhibition of geranylgeranylation and RhoA activation. Thus, statins, such as simvastatin, might be effective tools to antagonize CCL17-dependent migration and metastasis of colon cancer cells.

Keywords: Chemokines; Colon; Metastasis; Migration; Simvastatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Movement* / drug effects
  • Cell Movement* / physiology
  • Cell Proliferation / drug effects
  • Chemokine CCL17 / antagonists & inhibitors
  • Chemokine CCL17 / metabolism*
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology*
  • HT29 Cells
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Mevalonic Acid / pharmacology
  • Polyisoprenyl Phosphates / pharmacology
  • Prenylation
  • Receptors, CCR4 / metabolism
  • Simvastatin / pharmacology
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • CCL17 protein, human
  • CCR4 protein, human
  • Chemokine CCL17
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Polyisoprenyl Phosphates
  • Receptors, CCR4
  • RHOA protein, human
  • Simvastatin
  • Hydroxymethylglutaryl CoA Reductases
  • rhoA GTP-Binding Protein
  • geranylgeranyl pyrophosphate
  • Mevalonic Acid