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Genome-wide analysis of fatty acid synthase (FASN) gene silenced retinoblastoma cancer cells (WERI RB1) using cDNA microarray analysis

ABSTRACT: Fatty acid synthase is a major enzyme involved in de novo lipogenesis and associated with tumor invasion and poor prognosis. The effect of fatty acid synthase knockdown in retinoblastoma cancer cells (WERI RB1) using siRNA mediated gene silencing were accessed for global gene deregulations. The analysis resulted in RB cancer cell death through deregulations of various cell signalling, metabolic, immunity, angiogenesis, apoptosis and cell cycle pathway related genes. Further validations were done using qRT-PCR and western analysis. Our results provide evidence that blockade in lipid metabolism inturn lead to RB cancer cell death through impaired cell signalling pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63746 | GEO | 2015/12/01

SECONDARY ACCESSION(S): PRJNA268961

REPOSITORIES: GEO

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Project description:Chemotherapy resistance is one of the reasons for the loss of the eye in retinoblastoma (RB) pa-tients. RB chemotherapy resistance has been investigated in different cell culture models like WERI RB1. Furthermore, chemotherapy resistant RB subclones like the etoposide resistant WERI ETOR cell line have been established to improve understanding of chemotherapy resistance in RB. Ob-jective of this study was to characterize the cell line models of an etoposide sensitive WERI RB1 and its etoposide resistant subclone WERI ETOR by proteomics analysis. Subsequently, quantitative proteomic data served for correlation analysis with known drug perturbation profiles. . WERI RB1 and WERI ETOR were cultured and prepared for quantitative mass spectrometry. Comparative proteomic profiling was performed with electrospray ionization tandem mass spectrometry in data-independent acquisition mode (SWATH). The raw SWATH files were processed using neural networks in library free mode along with machine learning algorithms. Pathway enrichment was performed using the REACTOME pathway resource and correlated to the Molecular Signature Database (MSigDB) hallmark gene set collections for functional annotation. Also, a drug connec-tivity analysis using the L1000 database was used to correlate the mechanism-of-action (MOA) for different anticancer reagents to WERI RB1 / WERI ETOR signatures. A total 4,756 proteins were identified across all samples which revealed a distinct clustering between groups. Of these pro-teins, 64 proteins were significantly altered (q < 0.05 & log2FC |>2|, 22% higher in WERI ETOR). Pathway analysis showed an enriched metabolic pathway for retinoid metabolism and transport pathway in WERI ETOR and for sphingolipid de novo biosynthesis in WERI RB1. In addition, this study showed similar protein signatures of topoisomerase inhibitors and WERI ETOR as well as of ATPase inhibitors, acetylcholine receptor antagonists and VEGFR inhibitors and WERI RB1. In this study, WERI RB1 and WERI ETOR were characterized as a cell line model for chemotherapy re-sistance in RB by using data-independent mass spectrometry. The global proteome revealed the activation of sphingolipid de novo biosynthesis in WERI RB1 and potential treatment options for etoposide resistant RB.

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Genome-wide analysis of fatty acid synthase (FASN) gene silenced retinoblastoma cancer cells (WERI RB1) using cDNA microarray analysis

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