Suppressive effects of iron chelation in clear cell renal cell carcinoma and their dependency on VHL inactivation

Greene, Christopher J.; Sharma, Nitika; Fiorica, Peter N.; Forrester, Emily; Smith, Gary J.; Gross, Kenneth W.; Kauffman, Eric

doi:10.1016/j.freeradbiomed.2018.12.013

Cited by 18 publications

(18 citation statements)

References 105 publications

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“…A network analysis demonstrated that acetyl-CoA acetyltransferase (ACAT1) might be used to identify progression and predict the prognosis of ccRCC patients (L. Chen et al, 2019). (Greene et al, 2019). In the process of lipid peroxidation, β-oxidation and glutamine or cystine depletion is highly associated with ferroptosis in ccRCC cells (Miess et al, 2018).…”

Section: Lipids Metabolism and Rccmentioning

confidence: 99%

“…As a new form of cell death different from apoptosis and necrosis, ferroptosis is triggered by iron‐dependent oxidative damage, which involves iron metabolism and lipid peroxidation processes. A novel interplay between VHL/HIF‐α dysregulation and iron metabolism is characterized in ccRCC cells with high free iron levels, and iron deprivation by chelator drugs offers an effective therapeutic strategy for targeting HIF‐2α in ccRCC patients (Greene et al, 2019). In the process of lipid peroxidation, β‐oxidation and glutamine or cystine depletion is highly associated with ferroptosis in ccRCC cells (Miess et al, 2018).…”

Section: Tme and Metabolism In Rcc Therapymentioning

confidence: 99%

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The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy

Lai

Tang

Huang

et al. 2020

Journal Cellular Physiology

107

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Renal cell carcinoma (RCC) is one of the most common tumours of the urinary system, and is insidious and not susceptible to chemoradiotherapy. As the most common subtype of RCC (70-80% of cases), clear cell renal cell carcinoma (ccRCC) is characterized by the loss of von Hippel-Lindau and the accumulation of robust lipid and glycogen. For advanced RCC, molecular-targeted drugs, tyrosine kinase inhibitors (TKIs) and the immune checkpoint inhibitors (ICIs) have been increasingly recommended and investigated. Due to the existence of a highly dynamic, adaptive and heterogeneous tumour microenvironment (TME), and due to the glucose and lipid metabolism in RCC, this cancer may be accompanied by various types of resistance to TKIs and ICIs. With the increased production of lactate, nitric oxide, and other new by-products of metabolism, novel findings of the TME and key metabolic enzymes drived by HIF and other factors have been increasingly clarified in RCC carcinogenesis and therapy. However, there are few summaries of the TME and tumour metabolism for RCC progression and therapy. Here, we summarize and discuss the relationship of the important implicated characteristics of the TME as well as metabolic molecules and RCC carcinogenesis to provide prospects for future treatment strategies to overcome TME-related resistance in RCC.

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Section: Lipids Metabolism and Rccmentioning

confidence: 99%

Section: Tme and Metabolism In Rcc Therapymentioning

confidence: 99%

The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy

Lai

Tang

Huang

et al. 2020

Journal Cellular Physiology

107

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“…In renal cell carcinoma (RCC), analysis of iron metabolism genes, FPN, ferritin light and heavy chains, IRP2, and TfR1, revealed that these genes are all highly expressed in RCC, similar to other cancers, and TfR1 expression is used as a biomarker of RCC and is associated with worse survival outcomes (56). Iron levels are elevated in RCC as well as genes responsible for iron handling, where this cancer depends on iron for escape of apoptosis and cell cycle arrest.…”

Section: Kidney Cancermentioning

confidence: 99%

The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer

DeRosa

Leftin

2021

Front. Immunol.

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Macrophages fulfill central functions in systemic iron metabolism and immune response. Infiltration and polarization of macrophages in the tumor microenvironment is associated with differential cancer prognosis. Distinct metabolic iron and immune phenotypes in tumor associated macrophages have been observed in most cancers. While this prompts the hypothesis that macroenvironmental manifestations of dysfunctional iron metabolism have direct associations with microenvironmental tumor immune response, these functional connections are still emerging. We review our current understanding of the role of macrophages in systemic and microenvironmental immune response and iron metabolism and discuss these functions in the context of cancer and immunometabolic precision therapy approaches. Accumulation of tumor associated macrophages with distinct iron pathologies at the invasive tumor front suggests an “Iron Curtain” presenting as an innate functional interface between systemic and microenvironmental iron metabolism and immune response that can be harnessed therapeutically to further our goal of treating and eliminating cancer.

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“…ccRCC harbor the traits of primary resistance to chemotherapy and radiation therapy, mainly due to the dysregulation of vonhippel-lindau-hypoxia-inducible factorvascular endothelial growth factor (VHL-HIF-VEGF) pathway resulting from VHL gene mutation (Figure 7). Interestingly, the VHL-HIF-α axis participated in the government of iron metabolism inside ccRCC cells (50,51). VHL inactivation increases the sensitivity of ccRCC cell to ferroptosis, which is an iron-dependent form of programmed necrosis mainly triggered by extra-mitochondrial lipid peroxidation arising from an iron-dependent ROS accretion (52).…”

Section: Discussionmentioning

confidence: 99%

“…VHL inactivation increases the sensitivity of ccRCC cell to ferroptosis, which is an iron-dependent form of programmed necrosis mainly triggered by extra-mitochondrial lipid peroxidation arising from an iron-dependent ROS accretion (52). The survival, proliferation, and invasion ability of ccRCC cells were highly dependent on the elevated level of HIF-α and free iron concentration (50). Mounting evidences showed that the efficacy of drug targeting the VHL might be influenced by the turbulence of iron metabolism somewhat deriving from the abnormality of its related genes expression.…”

Section: Discussionmentioning

confidence: 99%

The Landscape of Iron Metabolism-Related and Methylated Genes in the Prognosis Prediction of Clear Cell Renal Cell Carcinoma

Mou

Zhang

et al. 2020

Front. Oncol.

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Background: Clear cell renal cell carcinoma (ccRCC) is characteristics of resistance to chemotherapy and radiotherapy. The prognosis of ccRCC was dismay with immense diversity. Iron metabolism disturbance is a common phenomenon in ccRCC. The purpose of our study is to identify and validate the candidate prognostic gene signature of iron metabolism and methylation closely related to the poor prognosis of ccRCC through comprehensive bioinformatics analysis in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Methods: The prognostic iron metabolism-related genes were screened according to the overlapping differentially expressed genes (DEGs) from the TCGA database. We built a prognostic model using risk score method to predict OS, each ccRCC patient's risk score was calculated, and the resulting score can divide these patients into two categories according to the cut-point risk score. The prognostic significance of the hub genes was further evaluated with the Kaplan-Meier (KM) survival and Receiver Operating Characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analysis was implemented to evaluate the impact of each variable on OS. Furthermore, the prediction power of the 25 gene signatures has been validated using an independent ccRCC cohort from the GEO database. The Gene Set Enrichment Analysis (GSEA) identified the characteristics of hub related oncogenes. Finally, we utilize Weighted Gene Co-expression Network Analysis (WGCNA) to investigate the co-expression network based on these DEGs. Results: In this study, we identified and validated 25 iron metabolism-related and methylated genes as the prognostic signatures, which differentiated ccRCC patients into high and low risk subgroups. The KM analysis showed that the survival rate of the high-risk patients was significantly lower than that of the low-risk patients. The risk score calculated with 25 gene signatures could largely predict OS and DFS for 1, 3, and 5 years in patients with ccRCC. Mou et al. Iron Metabolism Gene Predicts Prognosis in ccRCC Conclusions: Taken together, we identified the key iron metabolism-related and methylated genes for ccRCC through a comprehensive bioinformatics analysis. This study provides a reliable and robust gene signature for the prognostic predictor of ccRCC patients and maybe provides a promising treatment strategy for this lethal disease.

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Suppressive effects of iron chelation in clear cell renal cell carcinoma and their dependency on VHL inactivation

Cited by 18 publications

References 105 publications

The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy

The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy

The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer

The Landscape of Iron Metabolism-Related and Methylated Genes in the Prognosis Prediction of Clear Cell Renal Cell Carcinoma

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