Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment Journal Article
| Authors: | Sponagel, J.; Jones, J. K.; Frankfater, C.; Zhang, S.; Tung, O.; Cho, K.; Tinkum, K. L.; Gass, H.; Nunez, E.; Spitz, D. R.; Chinnaiyan, P.; Schaefer, J.; Patti, G. J.; Graham, M. S.; Mauguen, A.; Grkovski, M.; Dunphy, M. P.; Krebs, S.; Luo, J.; Rubin, J. B.; Ippolito, J. E. |
| Article Title: | Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment |
| Abstract: | Background: Brain 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. Methods: Using 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. Findings: We 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. Conclusion: Our 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. Funding: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund. © 2022 The Authors |
| Keywords: | brain tumor; glioma; brain neoplasms; mouse; animal; metabolism; animals; mice; diagnostic imaging; physiology; glutamic acid; glutamine; glutathione; sex characteristics; sex differences; citric acid cycle; cancer metabolism; solid-state nmr; tca cycle; humans; human; male; female; glutamine metabolism; pyruvate carboxylase; α-ketoglutarate; glutaminase; translation to patients; sexual characteristics |
| Journal Title: | Med |
| Volume: | 3 |
| Issue: | 11 |
| ISSN: | 2666-6359 |
| Publisher: | Cell Press |
| Date Published: | 2022-11-11 |
| Start Page: | 792 |
| End Page: | 811.e12 |
| Language: | English |
| DOI: | 10.1016/j.medj.2022.08.005 |
| PUBMED: | 36108629 |
| PROVIDER: | scopus |
| PMCID: | PMC9669217 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work