Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1

Abstract

Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been widely used to lower cholesterol and prevent cardiovascular diseases. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer, while the underlying mechanisms remain to be elucidated. Herein, we sought to investigate the effect of statins on the expression of pituitary tumor-transforming gene 1 (PTTG1), a critical gene involved in human breast cancer invasion and metastasis. Our results showed that PTTG1 is highly expressed in malignant Hs578T and MDA-MB-231 breast cancer cell lines as compared with normal or less malignant breast cancer cells. Furthermore, we found that the expression of PTTG1 was markedly suppressed by lipophilic statins, such as simvastatin, fluvastatin, mevastatin, and lovastatin, but not by hydrophilic pravastatin. In a dose and time dependent manner, simvastatin suppressed PTTG1 expression by decreasing PTTG1 mRNA stability in MDA-MB-231 cells. Both siRNA-mediated knockdown of PTTG1 expression and simvastatin treatment markedly inhibited MDA-MB-231 cell invasion, MMP-2 and MMP-9 activity, and the expression of PTTG1 downstream target genes, while ectopic expression of PTTG1 promoted cancer cell invasion, and partly reversed simvastatin-mediated inhibition of cell invasion. Mechanistically, we found that inhibition of PTTG1 expression by simvastatin was reversed by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate, suggesting the involvement of geranylgeranyl synthesis in regulating PTTG1 expression. Our results identified statins as novel inhibitors of PTTG1 expression in breast cancer cells and provide mechanistic insights into how simvastatin prevent breast cancer metastasis as observed in recent preclinical and clinical studies.

Statins: a repurposed drug to fight cancer

“…Lovastatin-induced MCF-7 cancer cell death is mediated via the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK)-p38 mitogen-activated protein kinase (p38MAPK)-p53-survivin signaling cascade [ 74 ]. Yin et al found that pituitary tumor-transforming gene 1 (PTTG1) was significantly overexpressed in malignant breast cancer cell lines, and simvastatin downregulates its expression by inhibiting GGPP [ 171 ]. Freed-Pastor et al revealed that mutant p53 can disrupt mammary acinar morphology by up-regulating the mevalonate pathway, thereby exerting a carcinogenic effect, while statins inhibit the mevalonate pathway to exert a tumor suppressor effect [ 172 ].…”

New Advances in Targeted Therapy of HER2-Negative Breast Cancer

“…A large number of statins, such as simvastatin, lovastatin and fluvastatin, can inhibit the proliferation and migration of breast cancer. The mechanisms related to their therapeutic effects include inhibition of PI3K/Akt and PPTG1 signaling pathways, activation of LKB1-AMPK-P38MAPK-p53-survivin cascade resulting in cell death, and increased caspase-3-mediated vimentin hydrolysis leading to the death of breast cancer cells (164)(165)(166)(167), indicating that it achieves the purpose of breast cancer treatment by regulating multiple signaling pathways.…”

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

“…Repurposing old drugs for antitumor therapy is an effective and economical way to develop new anticancer drugs. According to their original indications, we summarized these repurposing non-oncology small-molecule drugs for cancer therapy ( Table 1 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , <...>…”

“…3 , 16 ) and fluvastatin ( Fig. 4 , 17 ) can suppress the PI3K/AKT and RAS/ERK pathways to inhibit cancer 37 , 38 , 124 . Atorvastatin ( Fig.…”