Abstract
Malignant human anaplastic thyroid cancer (ATC) is pertinacious to conventional therapies. The present study investigated the anti-cancer activity of simvastatin and its underlying regulatory mechanism in cultured ATC cells. Simvastatin (0–20 μM) concentration-dependently reduced cell viability and relative colony formation. Depletions of mevalonate (MEV) and geranylgeranyl pyrophosphate (GGpp) by simvastatin induced G1 arrest and increased apoptotic cell populations at the sub-G1 phase. Adding MEV and GGpp prevented the simvastatin-inhibited cell proliferation. Immunoblotting analysis illustrated that simvastatin diminished the activation of RhoA and Rac1 protein, and this effect was prevented by pre-treatment with MEV and GGpp. Simvastatin increased the levels of p21cip and p27kip proteins and reduced the levels of hyperphosphorylated-Rb, E2F1 and CCND1 proteins. Adding GGpp abolished the simvastatin-increased levels of p27kip protein, and the GGpp-caused effect was abolished by Skp2 inhibition. Introduction of Cyr61 siRNA into ATC cells prevented the epidermal growth factor (EGF)-enhanced cell migration. The EGF-induced increases of Cyr61 protein expression and cell migration were prevented by simvastatin. Taken together, these results suggest that simvastatin induced ATC proliferation inhibition through the deactivation of RhoA/Rac1 protein and overexpression of p21cip and p27kip, and migration inhibition through the abrogation of Cyr61 protein expression.
Highlights
Human anaplastic thyroid cancer (ATC) is a highly aggressive and malignant disease
We showed that the simvastatin-induced prevention of degradation and increased expression of p27kip protein were reduced by geranylgeranyl pyrophosphate (GGpp) supplementation, and these effects caused by simvastatin were eliminated by the Skp2-specific inhibitor SKPin C1
The results from the present study indicate that the decreasing GGpp level is a key mechanism accounting for the anti-cancer effects of simvastatin in ATC
Summary
Human anaplastic thyroid cancer (ATC) is a highly aggressive and malignant disease. The survival time of patients since clinical diagnosis of the disease is 2–6 months only [1,2]. Observations from preclinical studies and clinical meta-analysis showed that the potent activity of statins, which inhibit the flux-initiating enzyme HMG-CoA reductase of the MEV pathway, could suppress the survival of cancer cells by inducing growth arrest and apoptosis [19,23]. These findings suggest that the MEV pathway is integral and drug-targetable for cancer therapy. Our results suggest that simvastatin reduced ATC cell proliferation via up-regulations of p21cip and p27kip expression, and migration via down-regulation of Cyr expression
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