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

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 me...

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Main Authors: Litian Yin, Zhongmei He, Bing Yi, Linyuan Xue, Jianxin Sun
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-11-01
Series:Frontiers in Pharmacology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fphar.2020.574068/full
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spelling doaj-b9bb9cc05f3649f3838131dd59eac3ad2020-11-25T04:08:08ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-11-011110.3389/fphar.2020.574068574068Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1Litian Yin0Litian Yin1Zhongmei He2Zhongmei He3Bing Yi4Linyuan Xue5Jianxin Sun6Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United StatesKey Laboratory for Cellular Physiology, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, ChinaCenter for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United StatesKey Laboratory for Cellular Physiology, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, ChinaCenter for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United StatesKey Laboratory for Cellular Physiology, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, ChinaCenter for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United StatesStatins, 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.https://www.frontiersin.org/articles/10.3389/fphar.2020.574068/fullpituitary tumor-transforming gene 1statinssimvastatinbreast cancercell migration
collection DOAJ
language English
format Article
sources DOAJ
author Litian Yin
Litian Yin
Zhongmei He
Zhongmei He
Bing Yi
Linyuan Xue
Jianxin Sun
spellingShingle Litian Yin
Litian Yin
Zhongmei He
Zhongmei He
Bing Yi
Linyuan Xue
Jianxin Sun
Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1
Frontiers in Pharmacology
pituitary tumor-transforming gene 1
statins
simvastatin
breast cancer
cell migration
author_facet Litian Yin
Litian Yin
Zhongmei He
Zhongmei He
Bing Yi
Linyuan Xue
Jianxin Sun
author_sort Litian Yin
title Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1
title_short Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1
title_full Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1
title_fullStr Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1
title_full_unstemmed Simvastatin Suppresses Human Breast Cancer Cell Invasion by Decreasing the Expression of Pituitary Tumor-Transforming Gene 1
title_sort simvastatin suppresses human breast cancer cell invasion by decreasing the expression of pituitary tumor-transforming gene 1
publisher Frontiers Media S.A.
series Frontiers in Pharmacology
issn 1663-9812
publishDate 2020-11-01
description 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.
topic pituitary tumor-transforming gene 1
statins
simvastatin
breast cancer
cell migration
url https://www.frontiersin.org/articles/10.3389/fphar.2020.574068/full
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