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

Priolo, Carmen; Khabibullin, Damir; Reznik, Ed; Filippakis, Harilaos; Ogórek, Barbara; Kavanagh, Taylor R.; Nijmeh, Julie; Herbert, Zachary T.; Asara, John M.; Kwiatkowski, David J.; Wu, Chin‐Lee; Henske, Elizabeth P.

doi:10.1073/pnas.1710849115

Cited by 59 publications

(69 citation statements)

References 33 publications

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“…We found that the expression of genes in glutathione (GSH) metabolism was dysregulated in RCC, which can affect the GSH levels and sensitivity to the oxidative stress. Our observations are consistent with recent studies focusing on glutathione metabolism in KICH 28,29 . We also observed that the pentose phosphatase pathway genes were upregulated in RCC.…”

Section: Discussionsupporting

confidence: 94%

Network-based metabolic characterization of renal cell carcinoma

Pandey

Lanke

Vinod

2020

Sci Rep

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An emerging hallmark of cancer is metabolic reprogramming, which presents opportunities for cancer diagnosis and treatment based on metabolism. We performed a comprehensive metabolic network analysis of major renal cell carcinoma (Rcc) subtypes including clear cell, papillary and chromophobe by integrating transcriptomic data with the human genome-scale metabolic model to understand the coordination of metabolic pathways in cancer cells. We identified metabolic alterations of each subtype with respect to tumor-adjacent normal samples and compared them to understand the differences between subtypes. We found that genes of amino acid metabolism and redox homeostasis are significantly altered in RCC subtypes. Chromophobe showed metabolic divergence compared to other subtypes with upregulation of genes involved in glutamine anaplerosis and aspartate biosynthesis. A difference in transcriptional regulation involving HIF1A is observed between subtypes. We identified E2F1 and FOXM1 as other major transcriptional activators of metabolic genes in RCC. Further, the co-expression pattern of metabolic genes in each patient showed the variations in metabolism within RCC subtypes. We also found that co-expression modules of each subtype have tumor stage-specific behavior, which may have clinical implications. Major biological processes namely reproduction, development, wound healing and tissue regeneration require cell proliferation. Cells proliferate in response to growth-promoting stimulus however, under adverse conditions they move into a reversible, non-proliferating state termed quiescence. Cells gauge the strength of proliferative and anti-proliferative signals through multiple molecular players to make cellular decisions. Cancer is a proliferative disease that arises when the regulatory control of quiescence-proliferation reversible transition is lost. An emerging hallmark of cancer is metabolic reprogramming, which helps to meet the energy demand for cell growth and division. Initial studies by Otto Warburg pointed to aerobic glycolysis, however recent advances have started to reveal other metabolic alterations and plasticity of cancer metabolism 1,2. Understanding the differences in metabolism between normal and cancer cells can shed light on the adaptations that promote disease progression and may also facilitate the identification of therapeutic metabolic targets. Mutations or epigenetic alterations in cancer can influence the expression of metabolic genes. Studies have explored transcriptome data of different cancers to understand the transcriptional dysregulation of metabolic genes. These studies are based on data generated by The Cancer Genome Atlas (TCGA) program. A pan-cancer analysis of different cancer types found a convergent metabolic landscape with upregulated nucleotide synthesis and downregulated mitochondrial metabolism as the main features 3. Rosario et al. 4 analyzed the gene expression of metabolic pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG) and found that pentose and glucuronate inter...

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Section: Discussionsupporting

confidence: 94%

Network-based metabolic characterization of renal cell carcinoma

Pandey

Lanke

Vinod

2020

Sci Rep

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“…The most strikingly increased set of metabolites in chRCC were those involved in glutathione metabolism (GSH, GSSG, γ-glutamyl-cysteine, Figure 2). This is similar to those previously identified in chRCC (Priolo et al, 2018), renal oncocytomas (Gopal et al, 2018;Kurschner et al, 2017), and in ccRCC (Hakimi et al, 2016;Wettersten et al, 2015). Since GSH is an important ROS scavenger (Circu and Aw, 2008) the increased GSH levels and GSH/GSSG ratios in chRCC can thus be considered as the main strategy for the tumor to overcome ROS stress originating from a dysregulated respiratory chain.…”

Section: Discussionsupporting

confidence: 85%

“…Recently, metabolome profiling in chRCC revealed an impairment of the gamma-glutamyl transferase 1 activity and significantly increased levels of reduced and oxidized glutathione in chRCC (Priolo et al, 2018). A similar rewiring of the glutathione metabolism was also identified in renal oncocytomas (Gopal et al, 2018;Kurschner et al, 2017).…”

Section: Introductionmentioning

confidence: 79%

“…Recently, a few studies, comprising roughly a hundred cases (Davis et al, 2014;Ricketts et al, 2018), were undertaken to understand the genetic cause of chRCC. In contrast, proteome and metabolome profiling data from this malignant tumor are still sparse (Priolo et al, 2018;Schaeffeler et al, 2018;Valera et al, 2010). To fill this gap, this study employs and integrates proteomics, transcriptomics (from TCGA), and metabolomic approaches as well as mitochondrial WES to gain insights into the mtDNA mutation landscape and to elucidate metabolic changes between chRCC and adjacent kidney tissues.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

Xiao

Clima

Busch

et al. 2019

Preprint

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Chromophobe renal cell carcinomas (chRCC) are derived from intercalated cells of the collecting duct system, and are thought to be the malignant counterpart of benign renal oncocytomas.Here, we report the characterization of nine chRCC with adjacent healthy kidney tissues by applying proteome-, transcriptome (TCGA)-, and metabolome profiling. Most strikingly, the reactive oxygen species scavenger glutathione was significantly elevated in chRCC, caused by down-regulated enzymes involved in glutathione degradation. Metabolic reprogramming including stalled gluconeogenesis, down-regulated fatty acid-and amino acid metabolism was identified, even though, the abundance of amino acids and "energy carrier" molecules were unchanged. A striking anti-correlation of the mitochondrial respiratory chain between the transcriptome and the proteome was discovered, the transcripts coding for the respiratory chain were up-, while corresponding proteins and enzymatic activities were down-regulated. Similar to renal oncocytomas, chRCC exhibited a significant increase in glutathione, but are distinguishable by distinct regulation of the respiratory chain.

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“…The most strikingly increased set of metabolites in pRCC were those involved in glutathione metabolism (GSH, GSSG, cysteine-glutathione disulfide, ophthalmic acid). This is similar to those previously identified in renal oncocytomas (17,55) and chRCC (27,56). GSH is an important ROS scavenger (57) and frequently produced by several tumor types to withstand unusual levels of oxidative stress (22).…”

Section: Discussionsupporting

confidence: 86%

Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

Alahmad

Paffrath

Clima

et al. 2019

Preprint

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Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, rewiring of the main pathways involved in ATP and glucose synthesis was observed at the protein level. In contrast, transcripts encoding for the respiratory chain were not regulated, which prompts for non-genetic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.

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

Cited by 59 publications

References 33 publications

Network-based metabolic characterization of renal cell carcinoma

Network-based metabolic characterization of renal cell carcinoma

Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

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