RRC ID 37063
Author Sangeetha M, Deepa PR, Rishi P, Khetan V, Krishnakumar S.
Title Global gene deregulations in FASN silenced retinoblastoma cancer cells: molecular and clinico-pathological correlations.
Journal J. Cell. Biochem.
Abstract Activation of fatty acid synthase (FASN) enzyme in the de novo lipogenic pathway has been reported in various cancers including retinoblastoma (RB), a pediatric ocular cancer. The present study investigates lipogenesis-dependent survival of RB cancer cells and the associated molecular pathways in FASN silenced RB cells. The siRNA-mediated FASN gene knockdown in RB cancer cells (Y79, WERI RB1) repressed FASN mRNA and protein expressions, and decreased cancer cell viability. Global gene expression microarray analysis was performed in optimized FASN siRNA transfected and untransfected RB cells. Deregulation of various downstream cell signaling pathways such as EGFR (n = 55 genes), TGF-beta (n = 45 genes), cell cycle (n = 41 genes), MAPK (n = 39 genes), lipid metabolism (n = 23 genes), apoptosis (n = 21 genes), GPCR signaling (n = 21 genes), and oxidative phosporylation (n = 18 genes) were observed. The qRT-PCR validation in FASN knockdown RB cells revealed up-regulation of ANXA1, DAPK2, and down-regulation of SKP2, SREBP1c, RXRA, ACACB, FASN, HMGCR, USP2a genes that favored the anti-cancer effect of lipogenic inhibition in RB. The expression of these genes in primary RB tumor tissues were correlated with FASN expression, based on their clinico-pathological features. The differential phosphorylation status of the various PI3K/AKT pathway proteins (by western analysis) indicated that the FASN gene silencing indeed mediated apoptosis in RB cells through the PI3K/AKT pathway. Scratch assay clearly revealed that FASN silencing reduced the invading property of RB cancer cells. Dependence of RB cancer cells on lipid metabolism for survival and progression is implicated. Thus targeting FASN is a promising strategy in RB therapy.
Volume 116(11)
Pages 2676-94
Published 2015-11
DOI 10.1002/jcb.25217
PMID 25958981
MeSH Cell Survival Child Child, Preschool Fatty Acid Synthase, Type I / genetics* Fatty Acid Synthase, Type I / metabolism* Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Humans Infant Lipogenesis* Male Oligonucleotide Array Sequence Analysis Retinal Neoplasms / genetics* Retinal Neoplasms / metabolism Retinal Neoplasms / pathology Retinoblastoma / genetics* Retinoblastoma / metabolism Retinoblastoma / pathology Signal Transduction
IF 2.959
Times Cited 4
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
Human and Animal Cells WERI-Rb-1(RCB2146)