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Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer.

Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer.
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Chen MC, Tsai YC, Tseng JH, Liou JJ, Horng S, Wen HC, Fan YC, Zhong WB, Hsu SP,


Chen MC, Tsai YC, Tseng JH, Liou JJ, Horng S, Wen HC, Fan YC, Zhong WB, Hsu SP, (click to view)

Chen MC, Tsai YC, Tseng JH, Liou JJ, Horng S, Wen HC, Fan YC, Zhong WB, Hsu SP,

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International journal of molecular sciences 2017 12 1318(12) pii 10.3390/ijms18122690

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.

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