Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells

• Published in: Cellular signalling 2003-03, Vol.15 (3), p.327-338
• Main Authors: Denoyelle, Christophe, Albanese, Patricia, Uzan, Georges, Hong, Li, Vannier, Jean-Pierre, Soria, Jeannette, Soria, Claudine
• Format: Article
• Language: English
• Subjects: ADP Ribose Transferases - pharmacology; AKT; Animals; Antineoplastic Agents - pharmacology; Botulinum Toxins - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer cell signalling; Cell Division - drug effects; Cell Membrane - metabolism; Cytosol - metabolism; FAK; Gene Expression Regulation, Neoplastic - drug effects; HMG-CoA reductase inhibitor; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Mice; Mice, Nude; Microarray; Neoplasm Invasiveness; Neovascularization, Pathologic - drug therapy; Oligonucleotide Array Sequence Analysis; Protein Prenylation - drug effects; Pyridines - pharmacology; RhoA; rhoA GTP-Binding Protein - metabolism; ROCK; Signal Transduction - drug effects; Tumor Cells, Cultured - cytology; Tumor Cells, Cultured - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/S0898-6568(02)00124-9

Statins are currently used for the treatment of hypercholesterolemia. Recently, we demonstrated that cerivastatin also reduces the proliferation and invasion of aggressive breast cancer cells, MDA-MB-231. In this report, a molecular mechanism to explain its anti-cancer action is proposed by combining the study of cerivastatin effect on both gene expression (microarray) and signal transduction pathways. Firstly, the expression of 13 genes was modified by cerivastatin and confirmed at protein level. They could contribute to the inhibition of both cell proliferation (down-regulation of cyclin D1, PCNA, c-myc and up-regulation p21 Waf1, p19 INK4d, integrin β8) and cell invasion, either directly (decrease in u-PA, MMP-9, u-PAR, PAI-1 and increase in anti-oncogenes Wnt-5a and H-cadherin) or indirectly by stimulating an anti-angiogenic gene (thrombospondin-2). The anti-angiogenic activity was confirmed by in vivo experiments. Secondly, we demonstrated that the biochemical mechanism of its anti-cancer action could be mainly explained by the inhibition of RhoA-dependent cell signalling. This hypothesis was supported by the fact that a RhoA inhibitor (C3 exoenzyme) or a dominant negative mutant RhoA (N19RhoA) induced similar effects to those of cerivastatin. In conclusion, cerivastatin, by preventing RhoA prenylation, inhibits (i) the RhoA/ROCK pathway, leading to defective actin stress fibres formation responsible for the loss of traction forces required for cell motility and (ii) the RhoA/FAK/AKT signalling pathway that could explain the majority of cancer-related gene modifications described above. Thus, the inhibition of RhoA cell signalling could be a good strategy in therapy of aggressive forms of breast cancer.