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

Abstract

IntroductionStatins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses.MethodsIn 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.ResultsLovastatin 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.ConclusionsThe 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.

Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent

“…Defective apoptosis has been reflected in the form of cell resistance to apoptotic inducing agents and, consequently, treatment failure. MVN has been suggested to induce cell death via multiple apoptotic 13 , necrotic 24 and autophagic pathways 14 . In the current work, MCF-7 seemed to undergo apoptosis by the p53-dependent pathway; however both Bcl 2 and BAX were not significantly affected (Figure 2).…”

“…However, the exact signaling mechanism of MVNinduced cell death remain controversial. Few reports attribute the anti-cancer activity of MVN to the induction of apoptosis 13 , while others negate any role of apoptosis in MVN-induced cell death 14 . Whether the apoptosis pathway is involved in MVN-induced cytotoxicity, or not, remained an open issue by 2011.…”

Biosynthesis of lovastatin using agro-industrial wastes as carrier substrates

“…In addition to treating hypercholesterolemia, lovastatin has other clinical applications for coronary heart disease, Alzheimer disease, renal diseases, cancer, bone fracture disease, and multiple sclerosis [8][9][10].…”

Inhibition of N-Myc down regulated gene 1 inin vitrocultured human glioblastoma cells

“…NDRG1 protein expression has been described to be present in normal brain or brain tumor tissue [11] as well as being an important gene that is playing an active role in the regulation of a broad spectrum of human cancer diseases like human gastric cancer, squamous cell carcinomas, breast cancer, human hepatocellular carcinoma, brain tumors and leukemia [12][13][14][15][16][17][18][19][20][21][22] . NDRG1 was suggested to be a prognostic marker for hypoxic regions within a tumor mass because of its stability as a protein [23][24][25] and because it is highly expressed in malignant tumor tissues compared to normal tissue of the same origin [26] .…”

“…g/mL streptomycin, and 100 units/mL penicillin). The pSUPER-NDRG1 vectors were designed as mentioned before [10][11][12][13][14][15][16][17] . To establish pSUPER-NDRG1, two sequences were selected from the human NDRG1 cDNA (5'-GCATTATTGGCAT-GGGAAC-3' (positions 398-416) and 5'-ATGCAGAG-TAACGTGGAAG-3' (positions 601 to 619), relative to the start codon).…”