Papillary Renal Cell Carcinomas Rewire Glutathione Metabolism and Are Deficient in Both Anabolic Glucose Synthesis and Oxidative Phosphorylation

Ahmad, Ayham Al; Paffrath, Vanessa; Clima, Rosanna; Busch, Jonas; Rabien, Anja; Kilic, Ergin; Villegas, Sonia L.; Timmermann, Bernd; Attimonelli, Marcella; Jung, Klaus; Meierhofer, David

doi:10.3390/cancers11091298

Cited by 21 publications

(16 citation statements)

References 72 publications

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“…1E), consistent with a previous study performed in chRCC (31). Interestingly, a similar pattern was reported in other RCC subtypes, including ccRCC (13), pRCC (32), and renal oncocytoma (17,33). Thus, the increase of glutathione has been proposed as a hallmark of kidney cancer and targeting glutathione metabolism can be exploited as a specific treatment strategy (34).…”

Section: Proteome and Metabolome Profiling Of Chrccsupporting

confidence: 89%

“…Kidney is the only organ, besides liver, that can deliver anabolic glucose for the organism, but a net flux can be generated only in one direction to avoid a futile cycle, which would violate thermodynamics. All kidney tumors seem to abandon this energy-consuming pathway since similar observations were also reported at the proteome level in renal oncocytomas (17), chRCC (49), and pRCC (32) and at the transcript level in pRCC (50) and ccRCC (30). A loss of differentiation, common in cancer, is indicated by the observed changes in the abundance of these gluconeogenic proteins.…”

Section: Discussionsupporting

confidence: 70%

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Endocytosis-Mediated Replenishment of Amino Acids Favors Cancer Cell Proliferation and Survival in Chromophobe Renal Cell Carcinoma

et al. 2020

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Chromophobe renal cell carcinoma (chRCC) accounts for approximately 5% of all renal cancers and around 30% of chRCC cases have mutations in TP53. ChRCC is poorly supported by microvessels and has markably lower glucose uptake than clear cell RCC (ccRCC) and papillary RCC (pRCC). Currently, the metabolic status and mechanisms by which this tumor adapts to nutrient-poor microenvironments remain to be investigated. In this study, we performed proteome and metabolome profiling of chRCC tumors and adjacent kidney tissues and identified major metabolic alterations in chRCC tumors, including the classical Warburg effect, the downregulation of gluconeogenesis and amino acid metabolism, and the upregulation of protein degradation and endocytosis. ChRCC cells depended on extracellular macromolecules as an amino acid source by activating endocytosis to sustain cell proliferation and survival. Inhibition of the PLCG2/IP3/Ca 2+ /PKC pathway significantly impaired the activation of endocytosis for amino acids uptakes into chRCC cells. In chRCC, whole-exome sequencing revealed that TP53 mutations were not related to expression of PLCG2 and activation of endocytosis. Our study provides novel perspectives on metabolic rewiring in chRCC and identifies the PLCG2/IP3/Ca 2+ /PKC axis as a potential therapeutic target in chRCC patients. Statement of Significance: This work reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner. Research.

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Section: Proteome and Metabolome Profiling Of Chrccsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 70%

Endocytosis-Mediated Replenishment of Amino Acids Favors Cancer Cell Proliferation and Survival in Chromophobe Renal Cell Carcinoma

et al. 2020

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“…Investigations have shown that increased expression of Talin-1 could lead to the progression of tumor cell adhesion and migration because of Talin-1 as a FA protein is able to mediate integrin interaction with ECM and can bind to a variety of adhesion molecules and induce cell cytoskeleton remodeling (23). B7-H3, also a member of the B7 family of immunoregulatory proteins which is overexpressed in many types of malignancies and is linked to poor prognosis, increased tumor grade, and metastasis (57).…”

Section: Discussionmentioning

confidence: 99%

High Cytoplasmic and Membranous Versus Nuclear Talin-1 Expression Associated With Malignancy Potential and Determine Survival and Metastasis of Clear Cell Renal Cell Carcinoma

Zanjani¹,

Vafaei²,

Abolhasani³

et al. 2020

Preprint

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Background: Talin-1 as a cytoskeleton protein participates in cell migration and has an essential role in cell adhesion, proliferation, tumorigenesis, invasion, and metastasis in various types of malignancies.Methods: Bioinformatics analysis has been performed by a using protein-protein interaction network, analyses among PRIDE databases, and indicated that Talin-1 protein as a potential prognostic focal adhesion factor in renal cell carcinoma (RCC). We, therefore, examined the protein expression levels and prognostic significance of Talin-1 with clinical follow-up in a total of 269 formalin-fixed paraffin-embedded tissue specimens from three important subtypes of RCC undergone radical nephrectomy and 30 adjacent normal tissues in three levels including, membrane, cytoplasm, and nucleus using immunohistochemistry on tissue microarrays. Then, we used a combined analysis with B7-H3 to confirm that Talin-1 may be related to metastasis.Results: The results showed that the expression of Talin-1 is significantly upregulated in most RCCs compared to adjacent normal tissues in protein levels. Further, there was a statistically significant difference between the membranous and cytoplasmic expression of Talin-1 and different subtypes of RCC (P < 0.001, P = 0.003, respectively). High membranous and cytoplasmic expression of Talin-1 was significantly associated with advanced nucleolar grade (P < 0.001, all), microvascular invasion (P = 0.007, P = 0.004), histological tumor necrosis (P = 0.020, P = 0.018), and invasion to Gerota’s fascia (P = 0.025, P = 0.050) in clear cell RCC (ccRCC). In addition, high membranous and cytoplasmic expression of Talin-1 was associated with significantly poorer disease-specific survival (DSS) (P = 0.043, P = 0.024, respectively) and progression-free survival (PFS) (P = 0.046, only in cytoplasmic expression). The co-expression of cytoplasmic Talin-1High /B7-H3High was observed to be associated with more aggressive tumor behavior and metastasis. Moreover, increased cytoplasmic expression of Talin-1High/B7-H3High compared to the other phenotypes was associated with poor prognosis and progression of the disease in patients with distant metastasis. Conclusion: Collectively, these observations indicate that Talin-1 is an important molecule involved in the spread and progression of ccRCC when expressed particularly in the cytoplasm and may serve as a novel prognostic biomarker in ccRCC if follow up time more prolonged.

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“…RCC are mostly consist of three subtypes, renal clear cell carcinoma (KIRC), renal papillary cell carcinoma (KIRP), and renal chromophobe cell carcinoma (KICH) 2 . Renal clear cell carcinoma (KIRC) constitutes 70 percent of all RCC cases, while renal papillary cell carcinoma (KIRP) is the second common subtype of RCC and occupies 15 percent 3 . Clinically, KIRP is considered as more inert than KIRC.…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins and Candidate Drugs in Renal Papillary Cell Carcinoma

Jiang¹,

Ren²,

Liu³

et al. 2020

Preprint

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Background: Roles of RNA binding proteins in renal papillary cell carcinoma (KIRP) remain undiscovered. We thus conducted a series of bioinformatics analyses to elucidate the associations between RBPs and prognosis of renal papillary cell carcinoma.Methods: RNA sequencing data and clinical of KIRP were downloaded from the TCGA database. The differentially expressed RBP coding genes (DEGs) were sorted out by R software and Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were then performed to evaluate the functional pathways. Protein-protein interaction (PPI) network of DEGs was formed through the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized by Cytoscape. Subsequently, a prognostic model was constructed by the uses of univariate Cox regression analysis, random survival forest analysis and multivariate Cox analysis. Validations of Receiver Operating Characteristic (ROC) analysis, KM analysis of overall survival and nomogram were performed as follow. Furthermore, CMap database was used to predict potential drugs.Results: A prognostic OS-predictive model based on six RBPs (SNRPN, RRS1, INTS8, RBPMS2, IGF2BP3 and PIH1D2) was constructed. STOCK1N-28457, pyrimethamine and trapidil were determined as potential drugs according to the CMap database.Conclusion: This study constructed a prognosis-related six-RBP signature and made a prediction of three small molecular drugs, which provided a novel insight into KIRP and assisted the development of individualized therapeutic strategies.

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Papillary Renal Cell Carcinomas Rewire Glutathione Metabolism and Are Deficient in Both Anabolic Glucose Synthesis and Oxidative Phosphorylation

Cited by 21 publications

References 72 publications

Endocytosis-Mediated Replenishment of Amino Acids Favors Cancer Cell Proliferation and Survival in Chromophobe Renal Cell Carcinoma

Endocytosis-Mediated Replenishment of Amino Acids Favors Cancer Cell Proliferation and Survival in Chromophobe Renal Cell Carcinoma

High Cytoplasmic and Membranous Versus Nuclear Talin-1 Expression Associated With Malignancy Potential and Determine Survival and Metastasis of Clear Cell Renal Cell Carcinoma

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins and Candidate Drugs in Renal Papillary Cell Carcinoma

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