Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma Journal Article


Authors: Priolo, C.; Khabibullin, D.; Reznik, E.; Filippakis, H.; Ogórek, B.; Kavanagh, T. R.; Nijmeh, J.; Herbert, Z. T.; Asara, J. M.; Kwiatkowski, D. J.; Wu, C. L.; Henske, E. P.
Article Title: Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma
Abstract: 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. © 2018 National Academy of Sciences. All Rights Reserved.
Keywords: oncocytoma; mitochondria; glutathione; chromophobe rcc; gamma-glutamyl cycle
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 115
Issue: 27
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2018-07-03
Start Page: E6274
End Page: E6282
Language: English
DOI: 10.1073/pnas.1710849115
PROVIDER: scopus
PUBMED: 29891694
PMCID: PMC6142242
DOI/URL:
Notes: Article -- Export Date: 1 August 2018 -- Source: Scopus
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  1. Eduard Reznik
    108 Reznik