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Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells
npj Systems Biology and Applications ( IF 4 ) Pub Date : 2021-01-08 , DOI: 10.1038/s41540-020-00161-7
Selva Rupa Christinal Immanuel 1, 2, 3 , Avinash D Ghanate 1, 2, 4 , Dharmeshkumar S Parmar 1, 2 , Ritu Yadav 1, 2 , Riya Uthup 1 , Venkateswarlu Panchagnula 1, 2 , Anu Raghunathan 1, 2
Affiliation  

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.



中文翻译:

综合遗传和代谢景观预测替莫唑胺抗性胶质母细胞瘤细胞的脆弱性

代谢重编程及其分子基础对于解开癌细胞功能和化学抗性的双重性至关重要。在这里,我们使用基于约束的综合方法来描绘代谢和表观遗传学之间的相互作用,在基因组中进行硬连线,以形成替莫唑胺 (TMZ) 抗性。在耐药性神经球体 (NSP) 和易感性 (U87MG) 胶质母细胞瘤细胞系中,针对不同浓度的 TMZ 确定了差异代谢。这种代谢适应的遗传基础以全外显子组测序为特征,该测序鉴定了生长和能量代谢的信号通路调节因子中的突变。值得注意的是,我们的综合方法确定了糖酵解、TCA 循环、苹果酸天冬氨酸分流和氧化磷酸化途径中的重新布线。50值为5 nM,比U87MG 的IC 50值为1.8 mM低三个数量级,因此使用我们的基于集成系统的方法确定。

更新日期:2021-01-08
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