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Published on: March 30, 2019
NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin
Sevtap Savas1, David O Azorsa, Hamdi Jarjanazi
1Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
Abstract:
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.
Insights
This study identified genes linked to resistance against simvastatin and lovastatin chemotherapy in cancer cells. Gene EAF2 was confirmed to influence cancer cell response to these statins.
Area of Science:
- Genomics
- Pharmacology
- Bioinformatics
Background:
- Simvastatin and lovastatin are cholesterol-lowering statins with potential anticancer properties.
- Understanding resistance mechanisms is crucial for their therapeutic application in oncology.
Purpose of the Study:
- To identify genes associated with resistance to simvastatin and lovastatin in cancer cells using bioinformatic analysis.
- To validate the role of identified genes in statin response.
Main Methods:
- Utilized publicly available NCI60 cell line data for pharmacological and genomic (Affymetrix 125K SNP) analysis.
- Performed whole-genome association studies to identify resistance-associated genes.
- Validated findings using RNA interference (RNAi) methodology.
Main Results:
- Identified three genes (NRP1, COL13A1, MRPS31) associated with simvastatin resistance.
- Identified six genes (EAF2, ANK2, AKAP7, STEAP2, LPIN2, PARVB) associated with lovastatin resistance.
- RNAi confirmed EAF2 silencing modulated HCT-116 colon cancer cell response to both statins.
Conclusions:
- Successfully employed whole-genome association studies on public data to find statin resistance genes.
- EAF2 plays a significant role in the cellular response to simvastatin and lovastatin in colon cancer cells.
