Savas, Sevtap and Azorsa, David O. and Gonzales, Irma M. and Arora, Silpi and Henderson, Meredith C. and Choi, Yun Hee and Briollais, Laurent and Ozcelik, Hilmi and Tuzmen, Sukru (2011) NCI60 Cancer Cell Line Panel Data and RNAi Analysis Help Identify EAF2 as a Modulator of Simvastatin and Lovastatin Response in HCT-116 Cells. PLoS ONE, 6 (4). pp. 1-12. ISSN 1932-6203
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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.
|Keywords:||Ankyrin 2, Collagen type 13 alpha 1, ELL associated factor 2, Lipin 2, Membrane protein, Mevinolin, Mitochondrial ribosomal protein S31, Neurophilin 1, Parvin beta, Protein kinase A anchor protein 7, Simvastatin, Six transmembrane epithelial antigen of the prostate 2, Unclassified drug, AKAP7 gene, ANK2 gene; article, Cancer cell culture, Cancer resistance, Cell strain, Cell strain HCT116, Cell strain NCI60, COL13A1 gene, Controlled study, Cytotoxicity, EAF2 gene, Gene, Gene frequency, Gene function, Gene identification, Gene interaction, Gene silencing, Genetic association, Genetic screening, Human, Human cell, Intron, LPIN2 gene, MRPS31 gene, NRP1 gene, PARVB gene, RNA interference, Single nucleotide polymorphism, STEAP2 gene|
|Department(s):||Medicine, Faculty of|
|Date:||4 April 2011|
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