Effects of lovastatin on breast cancer cells: a proteo-metabonomic study

• Type of Material: Article
• Authors: Jelena Klawitter, University of Colorado Denver; Touraj Shokati, University of Colorado Denver; Vanessa Moll, Emory University; Uwe Christians, University of Colorado Denver; Jost Klawitter, University of Colorado Denver
• Language: English
• Date: 2010-01-01
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2010 Klawitter et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://dx.doi.org/10.1186/bcr2485
• Title of Journal or Parent Work: Breast Cancer Research
• ISSN: 1465-5411
• Volume: 12
• Issue: 2
• Start Page: R16
• End Page: R16
• Grant/Funding Information: The authors would like to thank Eurofins Medinet Inc., Denver for providing technical and instrumental support. This work was supported by the United States National Institutes of Health, grants R01 HL071805 and P30 DK048520 (Mass Spectrometry Core).
• Keywords: COA REDUCTASE; OXIDATIVE STRESS; MEVALONATE PATHWAY; Science & Technology; STATIN USE; INDUCED APOPTOSIS; Oncology; Life Sciences & Biomedicine; MYELOID-LEUKEMIA CELLS; MAGNETIC-RESONANCE; TUMOR SUPPRESSION; PTEN; RHO-GTPASES
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Introduction: 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.