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Int. J. Mol. Sci. 2017, 18(12), 2690; https://doi.org/10.3390/ijms18122690

Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer

1
Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
4
Department of Neurosurgery, Taipei City Hospital, Renai Branch, Taipei 106, Taiwan
5
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
*
Authors to whom correspondence should be addressed.
Received: 23 October 2017 / Revised: 29 November 2017 / Accepted: 9 December 2017 / Published: 13 December 2017
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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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. View Full-Text
Keywords: simvastatin; RhoA; p21cip; p27kip; anaplastic thyroid cancer simvastatin; RhoA; p21cip; p27kip; anaplastic thyroid cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Chen, M.-C.; Tsai, Y.-C.; Tseng, J.-H.; Liou, J.-J.; Horng, S.; Wen, H.-C.; Fan, Y.-C.; Zhong, W.-B.; Hsu, S.-P. Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer. Int. J. Mol. Sci. 2017, 18, 2690.

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