Abstract
Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and is one of the leading causes of cancer-related death worldwide. Simvastatin, an HMG-CoA reductase inhibitor, which decreases cholesterol synthesis by inhibiting mevalonate pathways and is widely used to treat cardiovascular diseases. Simvastatin exhibits anticancer effects against several malignancies. However, the molecular mechanisms underlying the anticancer effects of simvastatin on HCC are still not well understood. In this study, we demonstrated simvastatin-induced G0/G1 arrest by inducing p21 and p27 accumulation in HepG2 and Hep3B cells. Simvastatin also promoted AMP-activated protein kinase (AMPK) activation, which induced p21 upregulation by increasing its transcription. Consistent with this finding, we found genetic silencing of AMPK reduced p21 expression; however, AMPK silencing had no effect on p27 expression in HCC cells. Simvastatin decreased Skp2 expression at the transcriptional level, which resulted in p27 accumulation by preventing proteasomal degradation, an effect mediated by signal transducer and activator of transcription 3 (STAT3) inhibition. Constitutive STAT3 activation maintained high-level Skp2 expression and lower level p27 expression and significantly prevented G0/G1 arrest in simvastatin-treated HCC cells. Mevalonate decreased simvastatin-induced AMPK activation and rescued phospho-STAT3 and Skp2 expression in HCC cells, which resulted in the prevention of G0/G1 arrest through inhibition of p21 and p27 accumulation. Moreover, simvastatin significantly decreased tumor growth in HepG2 xenograft mice. Consistently, we found that simvastatin also increased p21 and p27 expression in tumor sections by reducing Skp2 expression and inducing AMPK activation and STAT3 suppression in the same tumor tissues. Taken together, these findings are demonstrative of the existence of a novel pathway in which simvastatin induces G0/G1 arrest by upregulating p21 and p27 by activating AMPK and inhibiting the STAT3–Skp2 axis, respectively. The results identify novel targets that explain the beneficial anticancer effects of simvastatin treatment on HCC in vitro and in vivo.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide.[1,2] HCC is induced by multiple conditions, including hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcoholic liver disease and metabolic syndrome.[3]
The results showed that the decrease in HepG2 and Hep3B cell viability elicited by 5–20 μg/ml simvastatin treatment (Figure 1a) did not correspond to the cell death rate of both cells subjected to the same dosage of simvastatin treatment (Figure 1b)
These p21 and p27 knockdown cells rescued the G0/G1 cell population under simvastatin treatment (Figure 1g). These results indicated that simvastatin treatment-induced G0/G1 cell cycle arrest that was dependent on p21 and p27 accumulation in HepG2 cells
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide.[1,2] HCC is induced by multiple conditions, including hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcoholic liver disease and metabolic syndrome.[3]. In a previous study of patients with HBV- and HCVrelated HCC, we reported that antiviral therapy reduced HCC recurrence and mortality after liver resection or radiofrequency ablation.[5,6,7] antiviral therapy only reduces the risk of HCC. It does not eliminate the risk of the disease.
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