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.
journal_name
Biochem Biophys Res Communjournal_title
Biochemical and biophysical research communicationsauthors
Al-Haidari AA,Syk I,Thorlacius Hdoi
10.1016/j.bbrc.2014.02.078subject
Has Abstractpub_date
2014-03-28 00:00:00pages
68-72issue
1eissn
0006-291Xissn
1090-2104pii
S0006-291X(14)00349-0journal_volume
446pub_type
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journal_title:Biochemical and biophysical research communications
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