Glutathione Metabolism in Renal Cell Carcinoma Progression and Implications for Therapies

Xiao, Yi; Meierhofer, David

doi:10.3390/ijms20153672

Cited by 68 publications

(61 citation statements)

References 128 publications

(204 reference statements)

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“…This suggests possible alternative roles for CI mutations in OXPHOS or, as-yet unknown, compensatory mechanisms leading to increased transcript levels of OXPHOS-related factors. It was recently reported that chRCC and RO have elevated levels of GSH (24)(25)(26)(27)(28), which is a novel hallmark of all RCCs and a potential therapeutic target (29). Enhanced GSH biosynthesis in RO is presumed to be an adaptive event resulting from loss-of-function mutations in CI subunits (24,25).…”

Section: Introductionmentioning

confidence: 99%

Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

et al. 2020

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Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNAbut not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy. Significance: These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.

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Section: Introductionmentioning

confidence: 99%

Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

et al. 2020

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“…The resistance shown by these cells may be related to their high concentration of intracellular glutathione (GSH) . Renal carcinoma cells are known for producing a high concentration of intracellular glutathione (GSH) . This antioxidant protects cells from toxic effects of reactive species of oxygen (ROS) and elimination of xenobiotics.…”

Section: Introductionmentioning

confidence: 99%

“…Clear‐cell renal carcinoma is also considered a hypervascular tumor due to inactivation of the suppressor von Hippel Lindau gene that triggers the induction of proangiogenic factors, facilitating metastasis . All these factors make renal carcinoma an invasive and aggressive tumor . Herein, the focus was on some mechanisms responsible for the anticancer activity of many anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

“…[8] Renal carcinoma cells are known for producing a high concentration of intracellular glutathione (GSH). [9] This antioxidant protects cells from toxic effects of reactive species of oxygen (ROS) and elimination of xenobiotics. However, disulfides (RS-SR) and thiosulfonates (RS-S(O) 2 R) are able to act significantly through S-thiolation of GSH, leading to its oxidized form (RS-SG).…”

Section: Introductionmentioning

confidence: 99%

“…[14][15] All these factors make renal carcinoma an invasive and aggressive tumor. [9] Herein, the focus was on some mechanisms responsible for the anticancer activity of many anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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S‐(4‐Methoxyphenyl)‐4‐methoxybenzenesulfonothioate as a Promising Lead Compound for the Development of a Renal Carcinoma Agent

et al. 2020

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Organosulfur compounds show cytotoxic potential towards many tumor cell lines. Disulfides and thiosulfonates act through apoptotic processes, inducing proteins associated with apoptosis, endoplasmic reticulum stress, and the unfolded protein response. Three p‐substituted symmetric diaryl disulfides and three diaryl thiosulfonates were synthesized and analyzed for inhibition of tubulin polymerization and for human cancer cell cytotoxic activity against seven tumor cell lines and a non‐tumor cell line. S‐(4‐methoxyphenyl)‐4‐methoxybenzenesulfonothioate (6) exhibited inhibition of tubulin polymerization and showed the best antiproliferative potential, especially against the 786‐0 cell line, being six times more selective as compared with the non‐tumor cell line. In addition, compound 6 was able to activate caspase‐3 after 24 and 48 h treatments of the 786‐0 cell line and induced cell‐cycle arrest in the G2/M stage at the highest concentration evaluated at 24 and 48 h. Compound 6 was able to cause complete inhibition of proliferation, inducing the death of 786‐0 cells, by increasing the number of cells at G2/M and greater activation of caspase‐3.

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Identification and validation of m6A‐associated ferroptosis genes in renal clear cell carcinoma

Pang,

Zhao,

Dongye

et al. 2024

Cell Biology International

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Urinary cancer is synonymous with clear cell renal cell carcinoma (ccRCC). Unfortunately, existing treatments for this illness are ineffective and unpromising. Finding novel ccRCC biomarkers is crucial to creating successful treatments.The Cancer Genome Atlas provided clear cell renal cell carcinoma transcriptome data. Functional enrichment analysis was performed on ccRCC and control samples' differentially expressed N6‐methyladenosine RNA methylation and ferroptosis‐related genes (DEMFRGs). Machine learning was used to find and model ccRCC patients' predicted genes. A nomogram was created for clear cell renal cell carcinoma patients. Prognostic genes were enriched. We examined patients' immune profiles by risk score. Our prognostic genes predicted ccRCC treatment drugs.We found 37 DEMFRGs by comparing 1913 differentially expressed ccRCC genes to 202 m6A RNA methylation FRGs. Functional enrichment analysis showed that hypoxia‐induced cell death and metabolism pathways were the most differentially expressed methylation functional regulating genes. Five prognostic genes were found by machine learning: TRIB3, CHAC1, NNMT, EGFR, and SLC1A4. An advanced renal cell carcinoma nomogram with age and risk score accurately predicted the outcome. These five prognostic genes were linked to various cancers. Immunological cell number and checkpoint expression differed between high‐ and low‐risk groups. The risk model successfully predicted immunotherapy outcome, showing high‐risk individuals had poor results. NIACIN, TAE‐684, ROCILETINIB, and others treat ccRCC. We found ccRCC prognostic genes that work. This discovery may lead to new ccRCC treatments.

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Glutathione Metabolism in Renal Cell Carcinoma Progression and Implications for Therapies

Cited by 68 publications

References 128 publications

Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

S‐(4‐Methoxyphenyl)‐4‐methoxybenzenesulfonothioate as a Promising Lead Compound for the Development of a Renal Carcinoma Agent

Identification and validation of m6A‐associated ferroptosis genes in renal clear cell carcinoma

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