02198nas a2200289   4500008004100000022001400041245008700055210006900142260000800211300001400219490000800233520125800241653001401499653002301513653002501536653002001561653002801581653001001609100002901619700002501648700003001673700002001703700003101723700001701754700002101771856011601792       2018                        eng d  a0006-291X00aIntegrative analysis of rewired central metabolism in temozolomide resistant cells0 aIntegrative analysis of rewired central metabolism in temozolomi  cJAN  a2010-20160 v4953 a<p>An authenticated U87MG clonal glioblastoma cell line was investigated to identify a sub-population of neurospheroidal (NSP) cells within the main epithelial population (U87MG). The NSP cells sorted using Fluorescence Assisted Cell Sorting (FACS) showed varied morphology, 30% lower growth rates, 40% higher IC50 values for temozolomide drug and could differentiate into the glial cell type (NDx). Metabolite profiling using HR-LCMS identified glucose, glutamine and serine in both populations and tryptophan only in U87MG as growth limiting substrates. Glycine, alanine, glutamate and proline were secreted by U87MG, however proline and glycine were re-utilized in NSP. Exo-metabolite profiling and phenotypic microarrays identified differential metabolism of primary carbon sources glucose and derived pyruvate for U87MG; glutamine and derived glutamate metabolism in NSP. Differential mRNA abundance of AKT1, PTEN, PIK3CA controlling metabolism, drug efflux, nutrient transport and epigenetic control MDM2 are potentially critical in shaping DNA methylation effects of temozolomide. Our study provides a new insight into the combined effect of these factors leading to temozolomide resistance in NSP. (C) 2017 Elsevier Inc. All rights reserved.</p>10aGlutamine10aMetabolic rewiring10aMetabolite profiling10amRNA abundances10aTemozolomide resistance10aU87MG1 aImmanuel, Selva, Rupa C.1 aGhanate, Avinash, D.1 aParmar, Dharmeshkumar, S.1 aMarriage, Fiona1 aPanchagnula, Venkateswarlu1 aDay, Nap, J.1 aRaghunathan, Anu  uhttps://library.ncl.res.in/content/integrative-analysis-rewired-central-metabolism-temozolomide-resistant-cells01855nas a2200205   4500008004100000245011700041210006900158260000900227300000600236490000600242520110000248100003201348700002501380700003001405700001601435700001601451700003101467700002101498856013001519       2021                        eng d00aIntegrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells0 aIntegrated genetic and metabolic landscapes predict vulnerabilit  cJAN   a20 v73 a<p>Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, malate aspartate shunt, and oxidative phosphorylation pathways. The differential killing of TMZ resistant NSP by Rotenone at low concentrations with an IC50 value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC50 value of 1.8 mM was thus identified using our integrated systems-based approach.</p>
1 aImmanuel, Selva, Rupa Chris1 aGhanate, Avinash, D.1 aParmar, Dharmeshkumar, S.1 aYadav, Ritu1 aUthup, Riya1 aPanchagnula, Venkateswarlu1 aRaghunathan, Anu  uhttps://library.ncl.res.in/content/integrated-genetic-and-metabolic-landscapes-predict-vulnerabilities-temozolomide-resistant