Effects of lovastatin on breast cancer cells: a proteo-metabonomic study.
BACKGROUND
Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses.


METHODS
In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques.


RESULTS
Lovastatin inhibited proliferation of breast cancer cell lines. MDAMB231 cells were more sensitive to its effects, and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone. Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A (RhoA) leading to a decreased expression of its active, membrane-bound form. Its downstream targets cofilin, CDC42 and G3BP1 are members of the GTPase family affected by lovastatin. Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma (Rb). This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 (MCM7) and MutS homolog 2 (MSH2). Lovastatin also regulated the AKT-signaling pathway. Increased phosphatase and tensin homolog (PTEN) and decreased DJ-1 expression lead to a down-regulation of the active pAkt. Lovastatin's involvement in the AKT-signaling pathway was confirmed by an upregulation of its downstream target, tumor progressor NDRG1. Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity, and lipid biosynthesis.


CONCLUSIONS
The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin. Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells.
Klawitter
Jelena
J
Department of Anesthesiology, Clinical Research and Development, University of Colorado-Denver, 12401 East 17th Avenue, Aurora, CO 80045, USA. Jelena.Klawitter@ucdenver.edu
Shokati
Touraj
T
Moll
Vanessa
V
Christians
Uwe
U
Klawitter
Jost
J
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D002952:Citric Acid Cycle / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D018384:Oxidative Stress / Q000187:drug effects; D020543:Proteome / Q000032:analysis* / Q000145:classification / Q000378:metabolism; D040901:Proteomics / Q000379:methods*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020543:Proteome; D008148:Lovastatin