Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer

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.

Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells

“…Statins have shown chemoprevention and anticancer effects in a wide range of cancers, such as anaplastic thyroid cancer, liver cancer, bladder cancer, nasopharyngeal cancer, colon cancer, prostate cancer, oral cancer, ovarian cancer, breast cancer, brain cancer, lung cancer, and leukemia. The pleiotropic effects of statins have been observed in several cellular processes, such as cell cycle arrest [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], apoptosis [ 14 , 16 , 18 , 19 , 20 , 21 ], autophagy [ 22 ], migration [ 18 , 23 ], invasion [ 24 ], stemness, and metastasis [ 25 ]. In addition, the mevalonate pathway (MVP) has been demonstrated as playing an important role in modulating cancer development, because it controls the biosynthesis of cholesterol that is an essential component of cell membranes and as well as other precursors and metabolites [ 26 , 27 , 28 ].…”

“…Statins have been reported to inhibit cell proliferation mainly by negative regulation on cell cycle in several cancers. The suppression of cell cycle progression was achieved through the upregulation of cyclin-dependent kinase (CDK) inhibitors, mostly p21 and p27 [ 9 , 10 , 11 , 13 , 14 , 15 , 17 , 29 , 30 ]. These cell cycle-related tumor suppressor genes (TSGs) bind to cyclin-CDKs complexes and inhibit kinase activity, which leads to the cell cycle arrest [ 31 ].…”

“…One study reported the effect of simvastatin on p21 expression depending on AMPK activation in liver cancer cells [ 11 ]. Statins were also found to act as S-phase kinase-associated protein 2 (SKP2) inhibitors in several cancer cells, which resulted in p27 protein accumulation by preventing proteasomal degradation [ 11 , 13 , 14 , 15 ]. Interestingly, atorvastatin is able to inhibit DNMT1 and restore the p16 expression in normal vascular smooth muscle cells through the demethylation of the p16 promoter region [ 32 ].…”

Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors

“…1). Based on these results and on previous studies [16,[22][23][24], coupled to the fact that simvastatin was the statin most related to antitumor properties in preclinical and clinical studies [11,[33][34][35], prompted us to select the 10 µM dose of simvastatin for further experiments. We next tested the antitumor effects of simvastatin (10 µM) in primary cell cultures from different PitNETs subtypes.…”

The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease

“…Furthermore, we observed increased GGPPS expression in the skeletal muscles of mice with insulin resistance, and specific knockout of GGPPS in skeletal muscle improved systemic insulin sensitivity and glucose homeostasis by enhancing glucose uptake in skeletal muscle. These metabolic alterations mediated by ggpps knockout were achieved through decreased geranylgeranylation of RhoA, which further induced the phosphorylation of IRS-1 (28). Thus, the GGPPS/RhoA/Rho kinase/ IRS-1 pathway mediates lipid-induced systemic insulin resistance in obese mice (29).…”