Oncotarget

Research Papers:

The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer

Jessica E. Stine, Hui Guo, Xiugui Sheng, Xiaoyun Han, Monica N. Schointuch, Timothy P. Gilliam, Paola A. Gehrig, Chunxiao Zhou _ and Victoria L. Bae-Jump

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Oncotarget. 2016; 7:946-960. https://doi.org/10.18632/oncotarget.5834

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Abstract

Jessica E. Stine1,*, Hui Guo1,2,*, Xiugui Sheng2, Xiaoyun Han1,2, Monica N. Schointuch1, Timothy P. Gilliam1, Paola A. Gehrig1,3, Chunxiao Zhou1,3,#, Victoria L. Bae-Jump1,3,#

1Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA

2Department of Gynecologic Oncology, ShanDong Cancer Hospital & Institute, Jinan University, Jinan, P.R. China

3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

*These authors have contributed equally to this work

#This work was presented at the Society of Gynecologic Oncology’s Annual meeting on Women’s Cancer. Chicago, IL. March 2015

Correspondence to:

Victoria L. Bae-Jump, e-mail: [email protected]

Chunxiao Zhou, e-mail: [email protected]

Keywords: simvastatin, ovarian cancer, HMGCR, invasion, apoptosis

Received: June 19, 2015     Accepted: September 23, 2015     Published: October 16, 2015

ABSTRACT

Ovarian cancer is the 5th leading cause of cancer death among women in the United States. The mevalonate pathway is thought to be a potential oncogenic pathway in the pathogenesis of ovarian cancer. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor, is a widely used drug for inhibiting the synthesis of cholesterol and may also have anti-tumorigenic activity. Our goal was to evaluate the effects of simvastatin on ovarian cancer cell lines, primary cultures of ovarian cancer cells and in an orthotopic ovarian cancer mouse model. Simvastatin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, and caused cellular stress via reduction in the enzymatic activity of HMGCR and inhibition of the MAPK and mTOR pathways in ovarian cancer cells. Furthermore, simvastatin induced DNA damage and reduced cell adhesion and invasion. Simvastatin also exerted anti-proliferative effects on primary cell cultures of ovarian cancer. Treatment with simvastatin in an orthotopic mouse model reduced ovarian tumor growth, coincident with decreased Ki-67, HMGCR, phosphorylated-Akt and phosphorylated-p42/44 protein expression. Our findings demonstrate that simvastatin may have therapeutic benefit for ovarian cancer treatment and be worthy of further exploration in clinical trials.


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