LAUSR

Significance The mechanisms of chromophobe renal cell carcinoma (ChRCC) pathogenesis remain a key knowledge gap. Through metabolomics, this study uncovered a fundamental metabolic mechanism underlying the pathogenesis of ChRCC, with key therapeutic implications for this rare tumor type, for which there are currently no specific targeted therapies. Further understanding of the impact of glutathione salvage pathway on mitochondrial function, tumor progression, and targeted therapy can provide insight into other cancers characterized by aberrant glutathione salvage pathway. Chromophobe renal cell carcinoma (ChRCC) accounts for 5% of all sporadic renal cancers and can also occur in genetic syndromes including Birt–Hogg–Dube (BHD) and tuberous sclerosis complex (TSC). ChRCC has a distinct accumulation of abnormal mitochondria, accompanied by characteristic chromosomal imbalances and relatively few “driver” mutations. Metabolomic profiling of ChRCC and oncocytomas (benign renal tumors that share pathological features with ChRCC) revealed both similarities and differences between these tumor types, with principal component analysis (PCA) showing a distinct separation. ChRCC have a striking decrease in intermediates of the glutathione salvage pathway (also known as the gamma-glutamyl cycle) compared with adjacent normal kidney, as well as significant changes in glycolytic and pentose phosphate pathway intermediates. We also found that gamma glutamyl transferase 1 (GGT1), the key enzyme of the gamma-glutamyl cycle, is expressed at ∼100-fold lower levels in ChRCC compared with normal kidney, while no change in GGT1 expression was found in clear cell RCC (ccRCC). Significant differences in specific metabolite abundance were found in ChRCC vs. ccRCC, including the oxidative stress marker ophthalmate. Down-regulation of GGT1 enhanced the sensitivity to oxidative stress and treatment with buthionine sulfoximine (BSO), which was associated with changes in glutathione-pathway metabolites. These data indicate that impairment of the glutathione salvage pathway, associated with enhanced oxidative stress, may have key therapeutic implications for this rare tumor type for which there are currently no specific targeted therapies.