Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.

Autor:	Sponagel J; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Jones JK; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Frankfater C; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Biomedical Mass Spectrometry Resource, Washington University School of Medicine, St. Louis, MO 63110, USA., Zhang S; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Tung O; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Cho K; Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Tinkum KL; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Gass H; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Nunez E; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Spitz DR; Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52246, USA; Holden Comprehensive Cancer Center, Department of Pathology, University of Iowa, Iowa City, IA 52246, USA., Chinnaiyan P; Department of Radiation Oncology, Beaumont Health, Royal Oak, MI 48073, USA; Oakland University William Beaumont School of Medicine, Rochester, MI 48073, USA., Schaefer J; Department of Chemistry, Washington University, St. Louis, MO 63130, USA., Patti GJ; Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Graham MS; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Mauguen A; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Grkovski M; Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Dunphy MP; Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA., Krebs S; Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA., Luo J; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA., Rubin JB; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: rubin_j@wustl.edu., Ippolito JE; Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: ippolitoj@wustl.edu.
Jazyk:	angličtina
Zdroj:	Med (New York, N.Y.) [Med] 2022 Nov 11; Vol. 3 (11), pp. 792-811.e12. Date of Electronic Publication: 2022 Sep 14.
DOI:	10.1016/j.medj.2022.08.005
Abstrakt:	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. Competing Interests: Declarations of interests G.J.P. is a scientific advisor for Cambridge Isotope Laboratories. The Patti laboratory has a collaboration agreement with Agilent Technologies and Thermo Fisher Scientific. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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