NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells

• Published in: PloS one Vol. 6; no. 4; p. e18306
• Main Authors: Savas, Sevtap, Azorsa, David O, Jarjanazi, Hamdi, Ibrahim-Zada, Irada, Gonzales, Irma M, Arora, Shilpi, Henderson, Meredith C, Choi, Yun Hee, Briollais, Laurent, Ozcelik, Hilmi, Tuzmen, Sukru
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-04-2011; Public Library of Science (PLoS)
• Subjects: Analysis; Antilipemic agents; Apoptosis; Bioinformatics; Biology; Biosynthesis; Biotechnology; Breast cancer; Cancer; Cancer therapies; Chemotherapy; Cholesterol; Colon; Colon cancer; Colorectal cancer; Cytotoxicity; Data processing; Databases, Factual; Drug dosages; Drug resistance; Drug Resistance, Neoplasm - genetics; Drugs; Genes; Genetics; Genome-wide association studies; Genomes; Genomics; HCT116 Cells; Hospitals; HT29 Cells; Humans; Kinases; Leukemia; Lipids; Longitudinal studies; Lovastatin; Lovastatin - pharmacology; Medical research; Medicine; Metabolism; Metabolites; Mutation; Ovarian cancer; Pathology; Pharmaceuticals; Pharmacology; Polymorphism, Single Nucleotide - genetics; Proteins; RNA Interference; RNA, Small Interfering - genetics; RNA-mediated interference; Signal transduction; Simvastatin; Simvastatin - pharmacology; Single nucleotide polymorphisms; Single-nucleotide polymorphism; siRNA; Statins; Transcription Factors - deficiency; Transcription Factors - genetics; Tumor cell lines; Tumors; Canada; United States > US; Arizona
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018306

Simvastatin and lovastatin are statins traditionally used for lowering serum cholesterol levels. However, there exists evidence indicating their potential chemotherapeutic characteristics in cancer. In this study, we used bioinformatic analysis of publicly available data in order to systematically identify the genes involved in resistance to cytotoxic effects of these two drugs in the NCI60 cell line panel. We used the pharmacological data available for all the NCI60 cell lines to classify simvastatin or lovastatin resistant and sensitive cell lines, respectively. Next, we performed whole-genome single marker case-control association tests for the lovastatin and simvastatin resistant and sensitive cells using their publicly available Affymetrix 125K SNP genomic data. The results were then evaluated using RNAi methodology. After correction of the p-values for multiple testing using False Discovery Rate, our results identified three genes (NRP1, COL13A1, MRPS31) and six genes (EAF2, ANK2, AKAP7, STEAP2, LPIN2, PARVB) associated with resistance to simvastatin and lovastatin, respectively. Functional validation using RNAi confirmed that silencing of EAF2 expression modulated the response of HCT-116 colon cancer cells to both statins. In summary, we have successfully utilized the publicly available data on the NCI60 cell lines to perform whole-genome association studies for simvastatin and lovastatin. Our results indicated genes involved in the cellular response to these statins and siRNA studies confirmed the role of the EAF2 in response to these drugs in HCT-116 colon cancer cells.