title: The molecular mechanism of the anticancer effect of atorvastatin: DNA             microarray and bioinformatic analyses.
abstract: The aim of this study was to identify the molecular mechanisms and biological pathways associated with the anticancer effects of atorvastatin. For this purpose, we conducted cell-based microarray and bioinformatic analyses to determine the effect of atorvastatin exposure on endothelial cell response. The results of bioinformatic analysis performed using the Connectivity Map (cMap) to examine the atorvastatin-induced changes in gene expression in the human umbilical vein endothelial cell line, EA.hy926, indicated that treatment with 10 µM of atorvastatin for 24 h upregulated the expression of 295 genes and downregulated the expression of 354 genes by 2-fold compared to the control treatment. The gene set enrichment analysis (GSEA), the Database for Annotation, Visualization and Integrated Discovery (DAVID) pathway analysis, and Gene Ontology (GO) analysis of differentially expressed genes revealed that Kruppel-like factors (KLFs) and cell cycle-related genes were the genes most significantly affected by atorvastatin treatment. The upregulation of KLFs and the downregulation of the cell cycle-related genes, including cyclin (CCN)A2, CCNE2, CCNB1 and CCNB2, were validated by real-time polymerase chain reaction (RT-PCR). A comparison of the gene expression profile of atorvastatin-treated cells with that of the control cells and with that of 6,100 compounds in the cMap database revealed that the profile of atorvastatin-treated cells was highly similar to that of histone deacetylase (HDAC) inhibitor-treated cells. Therefore, these results suggest that atorvastatin acts as an HDAC, a G1/S (start) and a G2/M (mitosis) cell cycle inhibitor. These findings provide evidence of the feasibility of the use of atorvastatin as an anticancer drug.
authors: First Geriatric Cardiology Division, Chinese PLA General Hospital, Beijing 100853, PR China.
authors: Yan
authors: Y
authors: Gao
authors: Xue-Chun
authors: XC
authors: Lu
authors: Hong-Ying
authors: HY
authors: Yang
authors: Xian-Feng
authors: XF
authors: Liu
authors: Jian
authors: J
authors: Cao
authors: Li
authors: L
authors: Fan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002453:Cell Cycle; D002460:Cell Line; D019295:Computational Biology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051741:Kruppel-Like Transcription Factors; D011758:Pyrroles; D000069059:Atorvastatin