Anti-inflammatory effect of pitavastatin on NF-κB activated by TNF-α in hepatocellular carcinoma cells

As nuclear factor-kappa B (NF-κB) is essential for promoting inflammation-associated cancer, it is a potential target for cancer prevention in chronic inflammatory diseases. Here we examined the anti-inflammatory effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on NF-κB activated by TNF-α in hepatocellular carcinoma (HCC) cells. Western blot revealed that the treatment of Huh 7 cells with pitavastatin at 0.1 μM inhibited the nuclear expression of NF-κB p65 induced by TNF-α. Furthermore, electrophoretic mobility shift assay showed that after the cells were incubated with pitavastatin alone or with pitavastatin and TNF-α for 24 h, pitavastatin significantly decreased the DNA binding activity of NF-κB induced by TNF-α. Subsequently, luciferase assay revealed that pitavastatin suppressed the transcriptional activity of the NF-κB promoter, which was clearly related to the HMG-CoA reductase activity because the addition of mevalonic acid (MEV) elevated the TNF-α activity. Moreover, the Rho kinase inhibitor Y27632 had no major effect on the NF-κB inhibitory activity of pitavastatin. The inhibitory effect of pitavastatin is possibly independent of the Rho kinase pathway in inflammation-associated HCC cells is. Finally, the addition of TNF-α significantly increased IL-6 protein production, which was suppressed by the addition of pitavastatin. These results suggest that pitavastatin at a low dose (0.1 μM) inhibits NF-κB activation and decreases IL-6 production induced by TNF-α, and is therefore expected to be a new strategy for treating HCC.