title: HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Amr A
authors.initials: AA
authors.lastname: Al-Haidari
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: Ingvar
authors.initials: I
authors.lastname: Syk
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden. Electronic address: henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D054414:Chemokine CCL17 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019073:HT29 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D054876:Prenylation; D054398:Receptors, CCR4 / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C106230:CCL17 protein, human; C515354:CCR4 protein, human; D054414:Chemokine CCL17; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D054398:Receptors, CCR4; C066737:RHOA protein, human; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
keywords: Chemokines; Colon; Metastasis; Migration; Simvastatin