谷氨酰胺
谷氨酰胺酶
新陈代谢
柠檬酸循环
生物
基因敲除
谷氨酰胺分解
谷氨酸受体
胶质瘤
生物化学
内科学
癌症研究
氨基酸
医学
基因
受体
作者
Jasmin Sponagel,Jill K. Jones,Cheryl Frankfater,Shanshan Zhang,Olivia Tung,Kevin Cho,Kelsey L. Tinkum,Hannah Gass,Elena Núñez,Douglas R. Spitz,Prakash Chinnaiyan,Jacob Schaefer,Gary J. Patti,Maya Srikanth Graham,Audrey Mauguen,Milan Grkovski,Mark Dunphy,Simone Krebs,Jingqin Luo,Joshua B. Rubin,Joseph E. Ippolito
出处
期刊:Med
[Elsevier]
日期:2022-11-01
卷期号:3 (11): 792-811.e12
被引量:6
标识
DOI:10.1016/j.medj.2022.08.005
摘要
BackgroundBrain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.MethodsUsing positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity.FindingsWe found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition.ConclusionOur results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research.FundingThis work was supported by NIH grants, Joshua’s Great Things, the Siteman Investment Program, and the Barnard Research Fund.
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