Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

Abstract

Background: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.

Methods: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.

Results: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.

Conclusions: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.