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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.

SUBMITTER: Priolo C

PROVIDER: S-EPMC6142242 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Priolo Carmen C Khabibullin Damir D Reznik Ed E Filippakis Harilaos H Ogórek Barbara B Kavanagh Taylor R TR Nijmeh Julie J Herbert Zachary T ZT Asara John M JM Kwiatkowski David J DJ Wu Chin-Lee CL Henske Elizabeth P EP

Proceedings of the National Academy of Sciences of the United States of America 20180611 27

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 differen ...[more]

PMID: 29891694

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Project description:Background: Dementia, as a global public health problem, is becoming increasingly serious. As a precursor of dementia, mild cognitive impairment (MCI) plays an important role in the diagnosis and prevention of dementia. Recent studies have found a correlation between gamma-glutamyl transferase (GGT) levels and cognitive function in men. The relationship between GGT levels and cognitive function in women remains unclear because GGT activity and expression differ between the sexes. Method: We recruited a total of 2,943 Chinese women from Jidong and Taian in 2019. We grouped the participants according to GGT levels, diagnosed MCI using the Montreal Cognitive Assessment (MOCA) scale, and modeled the study outcomes using logistic regression to explore the relationship between GGT level and MCI. We also analyzed the interaction of obesity, sleep duration, and hyperuricemia with GGT in the development of MCI. Results: The prevalence of MCI increased with increasing GGT level, from the lowest quartile to the highest quartile of GGT: 8.4% (66/786), 14.2% (119/840), 17.6% (108/613), and 21.4% (151/704), respectively. At the same time, as GGT levels increased, so did the risk of MCI. In the fully adjusted model, compared with those for participants in the lowest GGT quartiles, the odds ratios (ORs), and 95% confidence intervals (CIs) for MCI for participants in the second, third, and fourth GGT quartiles were 1.49 (1.04-2.12), 1.53(1.06-2.21), and 1.88 (1.33-2.65), respectively. The risk of developing MCI was further increased in people with high GGT levels who were obese (OR = 1.96, 95% CI: 1.39-2.76, P < 0.001), slept less (OR = 1.91, 95% CI: 1.35-2.71, P < 0.001), had high levels of uric acid (OR = 1.55, 95% CI: 1.03-2.32, P < 0.001), or after menopause (OR = 2.92, 95% CI: 2.07-4.12, P < 0.001). Conclusion: We found that MCI is more common in women with elevated GGT levels, so GGT could be a potential diagnostic marker for MCI. Meanwhile, our findings indicated that women with high GGT levels had an increased risk of MCI when they were obese, sleep deprived, had high serum uric acid (SUA) levels or underwent menopause.

Project description:Gamma-glutamyl transferase (GGT) is a biomarker of inflammation, and is known to be associated with stroke and atrial fibrillation. Venous thromboembolism (VT), a not uncommon thrombotic disorder, shares similar mechanisms with other thrombotic disorders including these stroke and atrial fibrillation. Given these associations, we intended to investigate the potential association between variability in GGT and VT. The study included data from the National Health Insurance Service-Health Screening Cohort, comprising 1,085,105 participants with health examinations 3 or more times from 2003 to 2008. Variability indexes were the coefficient of variation, standard deviation, and variability independent of the mean. The occurrence of venous thromboembolism (VT) was defined with more than one claim of the following ICD-10 codes: deep VT (I80.2-80.3), pulmonary thromboembolism (I26), intraabdominal venous thrombosis (I81, I82.2, I82.3), or other VT (I82.8, I82.9). To determine the relationship of quartiles of GGT with incident VT risk, Kaplan-Meier survival curve and logrank test were used. Cox's proportional hazard regression was used to investigate the risk of VT occurrence by GGT quartile (Q1-Q4). A total of 1,085,105 subjects were incorporated in the analysis, and the average follow-up was 12.4 years (interquartile range 12.2-12.6). VT occurred in 11,769 (1.08%) patients. The GGT level was measured 5,707,768 times in this stud. Multivariable analysis showed that GGT variability were positively associated with the occurrence of VT. Compared to the Q1, the Q4 showed an adjusted HR of 1.15 (95% CI 1.09-1.21, p < 0.001) when using coefficient of variation, 1.24 (95% CI 1.17-1.31, p < 0.001) when using standard deviation, and 1.10 (95% CI 1.05-1.16, p < 0.001) when using variability independent of the mean. Increased variability of GGT may be related to an increased risk of VT. Maintaining a stable GGT level would be beneficial in reducing the risk of VT.

Project description:BackgroundGamma-glutamyl transferase (GGT) has recently been reported as a biomarker for cardiovascular (CVD) risk in general populations. We investigated the associations of GGT with cardio-metabolic diseases and CVD risk in South Africans living with HIV.MethodsIn this cross-sectional study, HIV-infected adults were randomly recruited across 17 HIV clinics in the Western Cape Province. Homeostatic model assessment for insulin resistance (HOMA-IR), hypertension, diabetes, metabolic syndrome by Joint Interim Statement criteria (JIS-MS), a ≥5% and ≥10% predicted risk for a CVD event within 10 years by the Framingham risk score (10-years-CVD risk) were computed. Associations between GGT and cardio-metabolic trait were explored using linear and binomial logistic regressions adjusted for age, gender, lifestyle behaviours and HIV-related characteristics.ResultsAmong 709 participants (561 women, mean age 38.6 years), log-GGT was positively associated with waist circumference (β=2.75; p<0.001), diastolic blood pressure (β=1.65; p=0.006), total cholesterol (β=0.21; p<0.001), low-density lipoprotein-cholesterol (β=0.16; p<0.001), high-density lipoprotein-cholesterol and log-triglycerides (both β=0.12; p<0.001), fasting plasma glucose (β=0.19; p=0.031), 2-hour-post-glucose-load plasma glucose (β=0.26; p=0.007), HOMA-IR (β=0.13; p=0.001), log-high-sensitivity C-reactive-protein (β=0.3; p<0.001) in linear regression analyses; with hypertension [OR=1.41 (95%CI, 1.13-1.75); p=0.001], JIS-MS [OR=1.33 (1.05-1.68); p=0.016], ≥5% 10-year-CVD risk [OR=1.55 (1.24-1.9400); p<0.001] and ≥10% 10-year-CVD risk [OR=1.56 (1.08-2.23); p=0.016] but not with diabetes [OR=1.24 (0.88-1.71), p=0.205] in logistic regression analyses.ConclusionsIn this study, GGT levels were associated with cardio-metabolic variables independent of HIV specific attributes. If confirmed in longitudinal studies, GGT evaluation maybe included in CVD risk monitoring strategies in people living with HIV.

Dataset Information

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

Publications

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

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