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Title: Simvastatin-induced breast cancer cell death and deactivation of PI3K/Akt and MAPK/ERK signalling are reversed by metabolic products of the mevalonate pathway
Authors: Wang, T 
Seah, S 
Loh, X 
Chan, C.-W 
Hartman, M 
Goh, B.-C 
Lee, S.-C 
Keywords: caspase 3
farnesyl diphosphate
geranylgeranyl pyrophosphate
Ki 67 antigen
mammalian target of rapamycin
mevalonic acid
mitogen activated protein kinase
mitogen activated protein kinase 1
mitogen activated protein kinase 3
phosphatidylinositol 3 kinase
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
protein kinase B
Raf protein
hydroxymethylglutaryl coenzyme A reductase inhibitor
mevalonic acid
mitogen activated protein kinase
MTOR protein, human
phosphatidylinositol 3 kinase
protein kinase B
target of rapamycin kinase
antineoplastic activity
breast cancer
breast cancer cell line
cell cycle
cell death
cell proliferation
clinical article
controlled study
enzyme inhibition
human cell
human tissue
in vitro study
prospective study
protein cleavage
protein dephosphorylation
signal transduction
Breast Neoplasms
cancer grading
Carcinoma, Ductal, Breast
Carcinoma, Lobular
drug effects
enzyme immunoassay
gene expression regulation
middle aged
tumor cell culture
tumor invasion
Western blotting
Blotting, Western
Breast Neoplasms
Carcinoma, Ductal, Breast
Carcinoma, Lobular
Extracellular Signal-Regulated MAP Kinases
Gene Expression Regulation, Neoplastic
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Immunoenzyme Techniques
Mevalonic Acid
Middle Aged
Mitogen-Activated Protein Kinases
Neoplasm Grading
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinases
Prospective Studies
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
Issue Date: 2016
Citation: Wang, T, Seah, S, Loh, X, Chan, C.-W, Hartman, M, Goh, B.-C, Lee, S.-C (2016). Simvastatin-induced breast cancer cell death and deactivation of PI3K/Akt and MAPK/ERK signalling are reversed by metabolic products of the mevalonate pathway. Oncotarget 7 (3) : 2532-2544. ScholarBank@NUS Repository.
Abstract: Statins purportedly exert anti-tumoral effects on breast cancer. However, the biologic mechanisms for these actions are not fully elucidated. The aims of this study were 1) to explore the effects of simvastatin on apoptosis, proliferation as well as PI3K/Akt/mTOR and MAPK/ERK pathway in a window-of-opportunity breast cancer trial; 2) to further confirm findings from the clinical trial by functional studies; 3) to explore the regulatory role of mevalonate pathway on the anti-tumoral effects of simvastatin. In clinical samples, simvastatin led to increase in cleaved caspase-3 (p = 0.002) and decreased trend for Ki67 (p = 0.245). Simvastatin markedly suppressed PI3K/Akt/mTOR signalling by activating PTEN (p = 0.005) and by dephosphorylating Akt (p = 0.002) and S6RP (p = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf (p = 0.018) and ERK1/2 (p = 0.002). In ER-positive (MCF- 7, T47D) and ER-negative (MDA-MB-231, BT-549) breast cancer cells, simvastatin treatment consistently induced apoptosis and inhibited proliferation by deregulating caspase cascades and cell cycle proteins in a dose dependent manner. Concordantly, simvastatin strongly suppressed PI3K/Akt/mTOR pathway by enhancing PTEN expression and by further sequentially dephosphorylating downstream cascades including Akt, mTOR, p70S6K, S6RP and 4E-BP1. Furthermore, simvastatin significantly inhibited MAPK/ERK pathway by dephosphorylating sequential cascades such as c-Raf, MEK1/2 and ERK1/2. These simvastatin anti-tumoral effects were reversed by metabolic products of the mevalonate pathway, including mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These findings shed light on the biological and potential anti-tumoral effects of simvastatin in breast cancer.
Source Title: Oncotarget
ISSN: 19492553
DOI: 10.18632/oncotarget.6304
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