Glioblastoma Exhibit Sex Differences in Branched-Chain Amino Acid Metabolism.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients exhibit a survival advantage. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. Amino acids, such as glutamine and the branched-chain amino acids (leucine, isoleucine, valine; BCAAs), play important roles in GBM as they are involved in biosynthesis, energetics, redox homeostasis, and mTOR signaling. Using murine transformed astrocytes, we recently discovered that male cells are more dependent on glutamine and utilize more glutamine to replenish biosynthetic pathways, including BCAA regeneration. BCAA regeneration (i.e., re-amination of branched-chain ketoacids to BCAA) is catalyzed by branched-chain aminotransferases (BCATs) and requires glutamate as a nitrogen donor. Importantly, BCAA regeneration has been linked to cancer progression and poor outcome. Using stable isotope glutamine labeling we found that male transformed astrocytes exhibit greater nitrogen transfer from glutamate onto branched-chain ketoacids to regenerate BCAAs. In line with increased glutamate utilization for BCAA regeneration via BCAT, we found that male transformed astrocytes exhibit greater BCAT1 protein expression levels. Concordantly, male transformed astrocytes are more sensitive to BCAA deprivation compared to female cells, indicating that BCAA metabolism may play a sex-specific role in GBM. Using human GBM surgical specimens, we found greater BCAA metabolite abundance in male GBM. Importantly, our findings on sex differences in BCAA abundance and dependency in GBM are in line with previous reports that show that BCAA abundance and utilization differ between males and females under normal physiological conditions. Together, these data suggest that male GBM are more dependent on BCAAs and that BCAT1 may play unique roles in male and female GBM metabolism. Our data highlight that GBM metabolism differs between males and females and underline the importance of considering sex in metabolic targeting approaches.
Sponagel J, Gass H, Cho K, Chinnaiyan P, Patti G, Rubin J, et al. Glioblastoma exhibit sex differences in branched-chain amino acid metabolism. Neuro-Oncology. 2022 Nov;24(Suppl 7):vii266. doi: 10.1093/neuonc/noac209.1028.
27th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, Tampa, FL, November 16-20, 2022.