Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 2/2010

Open Access 01-04-2010 | Research article

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

Authors: Jelena Klawitter, Touraj Shokati, Vanessa Moll, Uwe Christians, Jost Klawitter

Published in: Breast Cancer Research | Issue 2/2010

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Kumar AS, Benz CC, Shim V, Minami CA, Moore DH, Esserman LJ: Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol Biomarkers Prev. 2008, 17: 1028-1033. 10.1158/1055-9965.EPI-07-0726.CrossRefPubMed
2.
Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B: Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat. 2008, 109: 573-579. 10.1007/s10549-007-9683-8.CrossRefPubMed
3.
Cauley JA, Zmuda JM, Lui LY, Hillier TA, Ness RB, Stone KL, Cummings SR, Bauer DC: Lipid-lowering drug use and breast cancer in older women: a prospective study. J Womens Health (Larchmt). 2003, 12: 749-756. 10.1089/154099903322447710.CrossRef
4.
Boudreau DM, Gardner JS, Malone KE, Heckbert SR, Blough DK, Daling JR: The association between 3-hydroxy-3-methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women: a case-control study. Cancer. 2004, 100: 2308-2316. 10.1002/cncr.20271.CrossRefPubMed
5.
Larner J, Jane J, Laws E, Packer R, Myers C, Shaffrey M: A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. Am J Clin Oncol. 1998, 21: 579-583. 10.1097/00000421-199812000-00010.CrossRefPubMed
6.
Katz MS, Minsky BD, Saltz LB, Riedel E, Chessin DB, Guillem JG: Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys. 2005, 62: 1363-1370.CrossRefPubMed
7.
Sassano A, Platanias LC: Statins in tumor suppression. Cancer Lett. 2008, 260: 11-19. 10.1016/j.canlet.2007.11.036.CrossRefPubMed
8.
Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature. 1990, 343: 425-430. 10.1038/343425a0.CrossRefPubMed
9.
Etienne-Manneville S, Hall A: Rho GTPases in cell biology. Nature. 2002, 420: 629-635. 10.1038/nature01148.CrossRefPubMed
10.
Cafforio P, Dammacco F, Gernone A, Silvestris F: Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis. 2005, 26: 883-891. 10.1093/carcin/bgi036.CrossRefPubMed
11.
Graaf MR, Richel DJ, van Noorden CJ, Guchelaar HJ: Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat Rev. 2004, 30: 609-641. 10.1016/j.ctrv.2004.06.010.CrossRefPubMed
12.
Campbell MJ, Esserman LJ, Zhou Y, Shoemaker M, Lobo M, Borman E, Baehner F, Kumar AS, Adduci K, Marx C, Petricoin EF, Liotta LA, Winters M, Benz S, Benz CC: Breast cancer growth prevention by statins. Cancer Res. 2006, 66: 8707-8714. 10.1158/0008-5472.CAN-05-4061.CrossRefPubMed
13.
Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA. 1994, 91: 6379-6383. 10.1073/pnas.91.14.6379.CrossRefPubMedPubMedCentral
14.
Kotamraju S, Williams CL, Kalyanaraman B: Statin-induced breast cancer cell death: role of inducible nitric oxide and arginase-dependent pathways. Cancer Res. 2007, 67: 7386-7394. 10.1158/0008-5472.CAN-07-0993.CrossRefPubMed
15.
Takeda I, Maruya S, Shirasaki T, Mizukami H, Takahata T, Myers JN, Kakehata S, Yagihashi S, Shinkawa H: Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007, 98: 890-899. 10.1111/j.1349-7006.2007.00471.x.CrossRefPubMed
16.
Hirai A, Nakamura S, Noguchi Y, Yasuda T, Kitagawa M, Tatsuno I, Oeda T, Tahara K, Terano T, Narumiya S, Kohn LD, Saito Y: Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells. J Biol Chem. 1997, 272: 13-16. 10.1074/jbc.272.1.13.CrossRefPubMed
17.
18.
Biosciences A: Melanie: The 2D gel analysis software User Manual. 2004, Amersham Biosciences and Geneva Bioinformatics SA
19.
Laudi S, Steudel W, Jonscher K, Schoning W, Schniedewind B, Kaisers U, Christians U, Trump S: Comparison of lung proteome profiles in two rodent models of pulmonary arterial hypertension. Proteomics. 2007, 7: 2469-2478. 10.1002/pmic.200600848.CrossRefPubMed
20.
Havlis J, Thomas H, Sebela M, Shevchenko A: Fast-response proteomics by accelerated in-gel digestion of proteins. Anal Chem. 2003, 75: 1300-1306. 10.1021/ac026136s.CrossRefPubMed
21.
Serkova N, Brand A, Christians U, Leibfritz D: Evaluation of the effects of immunosuppressants on neuronal and glial cells in vitro by multinuclear magnetic resonance spectroscopy. Biochim Biophys Acta. 1996, 1314: 93-104. 10.1016/S0167-4889(96)00081-X.CrossRefPubMed
22.
Klawitter J, Kominsky DJ, Brown JL, Klawitter J, Christians U, Leibfritz D, Melo JV, Eckhardt SG, Serkova NJ: Metabolic characteristics of imatinib resistance in chronic myeloid leukaemia cells. Br J Pharmacol. 2009, 158: 588-600. 10.1111/j.1476-5381.2009.00345.x.CrossRefPubMedPubMedCentral
23.
Kominsky DJ, Klawitter J, Brown JL, Boros LG, Melo JV, Eckhardt SG, Serkova NJ: Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL-positive cells. Clin Cancer Res. 2009, 15: 3442-3450. 10.1158/1078-0432.CCR-08-3291.CrossRefPubMed
24.
Klawitter J, Anderson N, Klawitter J, Christians U, Leibfritz D, Eckhardt SG, Serkova NJ: Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study. Br J Cancer. 2009, 100: 923-931. 10.1038/sj.bjc.6604946.CrossRefPubMedPubMedCentral
25.
Zwingmann C, Leibfritz D, Hazell AS: Energy metabolism in astrocytes and neurons treated with manganese: relation among cell-specific energy failure, glucose metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis. J Cereb Blood Flow Metab. 2003, 23: 756-771. 10.1097/01.WCB.0000056062.25434.4D.CrossRefPubMed
26.
Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF: Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. Hepatology. 2003, 37: 420-428. 10.1053/jhep.2003.50052.CrossRefPubMed
27.
Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG: Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov. 2007, 6: 541-555. 10.1038/nrd2221.CrossRefPubMed
28.
Swanson KM, Hohl RJ: Anti-cancer therapy: targeting the mevalonate pathway. Curr Cancer Drug Targets. 2006, 6: 15-37. 10.2174/156800906775471743.CrossRefPubMed
29.
Lei M: The MCM complex: its role in DNA replication and implications for cancer therapy. Curr Cancer Drug Targets. 2005, 5: 365-380. 10.2174/1568009054629654.CrossRefPubMed
30.
Istvan ES, Deisenhofer J: Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001, 292: 1160-1164. 10.1126/science.1059344.CrossRefPubMed
31.
32.
Dimitroulakos J, Ye LY, Benzaquen M, Moore MJ, Kamel-Reid S, Freedman MH, Yeger H, Penn LZ: Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clin Cancer Res. 2001, 7: 158-167.PubMed
33.
Hancock JF, Magee AI, Childs JE, Marshall CJ: All ras proteins are polyisoprenylated but only some are palmitoylated. Cell. 1989, 57: 1167-1177. 10.1016/0092-8674(89)90054-8.CrossRefPubMed
34.
35.
Casey PJ, Thissen JA, Moomaw JF: Enzymatic modification of proteins with a geranylgeranyl isoprenoid. Proc Natl Acad Sci USA. 1991, 88: 8631-8635. 10.1073/pnas.88.19.8631.CrossRefPubMedPubMedCentral
36.
Zhong WB, Wang CY, Chang TC, Lee WS: Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. Endocrinology. 2003, 144: 3852-3859. 10.1210/en.2003-0098.CrossRefPubMed
37.
Javanmoghadam-Kamrani S, Keyomarsi K: Synchronization of the cell cycle using lovastatin. Cell Cycle. 2008, 7: 2434-2440.CrossRefPubMed
38.
Wong WW, Clendening JW, Martirosyan A, Boutros PC, Bros C, Khosravi F, Jurisica I, Stewart AK, Bergsagel PL, Penn LZ: Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma. Mol Cancer Ther. 2007, 6: 1886-1897. 10.1158/1535-7163.MCT-06-0745.CrossRefPubMed
39.
Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD, Penn LZ: Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia. 2001, 15: 1398-1407. 10.1038/sj.leu.2402196.CrossRefPubMed
40.
Coleman ML, Olson MF: Rho GTPase signalling pathways in the morphological changes associated with apoptosis. Cell Death Differ. 2002, 9: 493-504. 10.1038/sj.cdd.4400987.CrossRefPubMed
41.
Fritz G, Just I, Kaina B: Rho GTPases are over-expressed in human tumors. Int J Cancer. 1999, 81: 682-687. 10.1002/(SICI)1097-0215(19990531)81:5<682::AID-IJC2>3.0.CO;2-B.CrossRefPubMed
42.
Etienne-Manneville S: Cdc42--the centre of polarity. J Cell Sci. 2004, 117: 1291-1300. 10.1242/jcs.01115.CrossRefPubMed
43.
Tocque B, Delumeau I, Parker F, Maurier F, Multon MC, Schweighoffer F: Ras-GTPase activating protein (GAP): a putative effector for Ras. Cell Signal. 1997, 9: 153-158. 10.1016/S0898-6568(96)00135-0.CrossRefPubMed
44.
45.
Fernandez-Hernando C, Suarez Y, Lasuncion MA: Lovastatin-induced PC-12 cell differentiation is associated with RhoA/RhoA kinase pathway inactivation. Mol Cell Neurosci. 2005, 29: 591-602. 10.1016/j.mcn.2005.04.012.CrossRefPubMed
46.
Luo Y, Hurwitz J, Massague J: Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature. 1995, 375: 159-161. 10.1038/375159a0.CrossRefPubMed
47.
Gehen SC, Vitiello PF, Bambara RA, Keng PC, O'Reilly MA: Downregulation of PCNA potentiates p21-mediated growth inhibition in response to hyperoxia. Am J Physiol Lung Cell Mol Physiol. 2007, 292: L716-724. 10.1152/ajplung.00135.2006.CrossRefPubMed
48.
Sanchez CA, Rodriguez E, Varela E, Zapata E, Paez A, Masso FA, Montano LF, Lopez-Marure R: Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Cancer Invest. 2008, 1-
49.
Sanchez CA, Rodriguez E, Varela E, Zapata E, Paez A, Masso FA, Montano LF, Loopez-Marure R: Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Cancer Invest. 2008, 26: 698-707. 10.1080/07357900701874658.CrossRefPubMed
50.
Sivaprasad U, Abbas T, Dutta A: Differential efficacy of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors on the cell cycle of prostate cancer cells. Mol Cancer Ther. 2006, 5: 2310-2316. 10.1158/1535-7163.MCT-06-0175.CrossRefPubMed
51.
Cortez D, Glick G, Elledge SJ: Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc Natl Acad Sci USA. 2004, 101: 10078-10083. 10.1073/pnas.0403410101.CrossRefPubMedPubMedCentral
52.
Chang IY, Jin M, Yoon SP, Youn CK, Yoon Y, Moon SP, Hyun JW, Jun JY, You HJ: Senescence-dependent MutS alpha dysfunction attenuates mismatch repair. Mol Cancer Res. 2008, 6: 978-989. 10.1158/1541-7786.MCR-07-0380.CrossRefPubMed
53.
Montesano Gesualdi N, Chirico G, Pirozzi G, Costantino E, Landriscina M, Esposito F: Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress. 2007, 10: 342-350. 10.1080/10253890701314863.CrossRefPubMed
54.
Song JY, Lim JW, Kim H, Morio T, Kim KH: Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells. J Biol Chem. 2003, 278: 36676-36687. 10.1074/jbc.M303692200.CrossRefPubMed
55.
Warburg O: On the origin of cancer cells. Science. 1956, 123: 309-314. 10.1126/science.123.3191.309.CrossRefPubMed
56.
Plas DR, Thompson CB: Akt-dependent transformation: there is more to growth than just surviving. Oncogene. 2005, 24: 7435-7442. 10.1038/sj.onc.1209097.CrossRefPubMed
57.
Li X, Lin G, Wu B, Zhou X, Zhou K: Overexpression of PTEN induces cell growth arrest and apoptosis in human breast cancer ZR-75-1 cells. Acta Biochim Biophys Sin (Shanghai). 2007, 39: 745-750. 10.1111/j.1745-7270.2007.00337.x.CrossRef
58.
Cantley LC, Neel BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 1999, 96: 4240-4245. 10.1073/pnas.96.8.4240.CrossRefPubMedPubMedCentral
59.
Mensah K, Mocanu MM, Yellon DM: Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: a potential role for phosphatase and tensin homolog deleted on chromosome ten?. J Am Coll Cardiol. 2005, 45: 1287-1291. 10.1016/j.jacc.2005.01.021.CrossRefPubMed
60.
Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C: Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Int J Cancer. 2006, 118: 2390-2398. 10.1002/ijc.21799.CrossRefPubMed
61.
Teresi RE, Planchon SM, Waite KA, Eng C: Regulation of the PTEN promoter by statins and SREBP. Hum Mol Genet. 2008, 17: 919-928. 10.1093/hmg/ddm364.CrossRefPubMed
62.
Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, DeLuca C, Liepa J, Zhou L, Snow B, Binari RC, Manoukian AS, Bray MR, Liu FF, Tsao MS, Mak TW: DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell. 2005, 7: 263-273. 10.1016/j.ccr.2005.02.010.CrossRefPubMed
63.
Davidson B, Hadar R, Schlossberg A, Sternlicht T, Slipicevic A, Skrede M, Risberg B, Florenes VA, Kopolovic J, Reich R: Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma. Hum Pathol. 2008, 39: 87-95. 10.1016/j.humpath.2007.05.014.CrossRefPubMed
64.
Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H: DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun. 1997, 231: 509-513. 10.1006/bbrc.1997.6132.CrossRefPubMed
65.
Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D, Watabe M, Gross S, Wang Y, Huggenvik J, Watabe K: PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res. 2004, 64: 7655-7660. 10.1158/0008-5472.CAN-04-1623.CrossRefPubMed
66.
Baum CL, Reschly EJ, Gayen AK, Groh ME, Schadick K: Sterol carrier protein-2 overexpression enhances sterol cycling and inhibits cholesterol ester synthesis and high density lipoprotein cholesterol secretion. J Biol Chem. 1997, 272: 6490-6498. 10.1074/jbc.272.10.6490.CrossRefPubMed
67.
Frolov A, Miller K, Billheimer JT, Cho TH, Schroeder F: Lipid specificity and location of the sterol carrier protein-2 fatty acid-binding site: a fluorescence displacement and energy transfer study. Lipids. 1997, 32: 1201-1209. 10.1007/s11745-997-0154-5.CrossRefPubMed
Metadata
Title
Effects of lovastatin on breast cancer cells: a proteo-metabonomic study
Authors
Jelena Klawitter
Touraj Shokati
Vanessa Moll
Uwe Christians
Jost Klawitter
Publication date
01-04-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 2/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2485

Other articles of this Issue 2/2010

Breast Cancer Research 2/2010 Go to the issue

Editorial

Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic?

Research article

Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study

Viewpoint

Interfering with inflammation: a new strategy to block breast cancer self-renewal and progression?

Review

MicroRNAs and their target gene networks in breast cancer

Research article

Management of anastrozole-induced bone loss in breast cancer patients with oral risedronate: results from the ARBI prospective clinical trial

Editorial

Radiation resistance in breast cancer: are CD44+/CD24-/proteosomelow/PKH26+cells to blame?
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits