Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

Aboud, Omran Abu; Habib, Samy L.; Trott, Josephine F.; Stewart, Benjamin; Liang, Sitai; Chaudhari, Abhijit J.; Sutcliffe, Julie L.; Weiss, Robert H.

doi:10.1158/0008-5472.can-17-0930

Cited by 92 publications

(92 citation statements)

References 57 publications

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“…This is in agreement with another study, which found that glutamine dependence in ccRCC suppresses oxidative stress (58). The inhibition of GSH synthesis by a specific glutaminase (GLS) inhibitor and the simultaneous treatment with hydrogen peroxide resulted in a high apoptosis rate in ccRCC (58). Hence, additional administrationof antioxidants during (chemotherapeutic) cancer treatment have been frequently shown to have no or even pro-tumor effects (59,60).…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…Other hematological malignancies, such as multiple myeloma, have been reported to be highly dependent on glutamine metabolism 33,34 . Furthermore, subsets of many solid tumor types, including lung, breast, kidney, and prostate cancer, have been shown to be susceptible to glutaminase inhibition [35][36][37][38][39][40] . Therefore, the use of a glutaminase inhibitor in combination with a pro-oxidant drug could represent a strategy with broad therapeutic utility in the treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

Targeting glutamine metabolism and redox state for leukemia therapy

Gregory

Nemkov

Zaberezhnyy

et al. 2018

Preprint

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Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional genotoxic chemotherapy and a diagnosis of AML is usually fatal.More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. Here, we show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating acute lymphoblastic leukemia cells in vitro and in vivo. Thus, targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia. Key Points• Glutaminase inhibition commonly impairs glutathione metabolism and induces mitochondrial oxidative stress in acute myeloid leukemia cells • A glutaminase inhibitor synergizes with pro-oxidant drugs in inducing apoptosis and eliminating leukemia cells in vitro and in vivo Homoharringtonine (HHT; omacetaxine mepesuccinate), arsenic trioxide (ATO), cell-permeable glutathione reduced ethyl ester (GSH-MEE) and dimethyl 2oxoglutarate (α-ketoglutarate) were purchased from Millipore Sigma. Metabolic tracing experimentsCells were seeded at 3 x 10 5 /ml (replicates of 3) and treated with vehicle (DMSO) or CB-839 at 500 nM for 8 h, followed by incubation in glutamine-free RPMI 1640 supplemented with 13 C 5 , 15 N 2 -labeled L-glutamine (Cambridge Isotope Laboratories) for up to 12 h, in the presence of vehicle or drug. Flash frozen cell pellets (~ 1 x 10 6 cells) or supernatants (50 µl) were extracted and subjected to analysis by ultra-high pressure liquid chromatography and mass spectrometry (UHPLC/MS) as was previously described 20 . Metabolite assignments, isotopologue distributions, and correction for expected natural abundances of 13 C and 15 N isotopes were performed using MAVEN (Princeton University, Princeton, NJ) and manually validated. Cell viability assaysCells were seeded at 0.5-1.0 x10 5 /ml in triplicate wells of 48-well tissue culture plates. Where indicated, the cells were treated with drug for a period of 48-72 h.After treatment, a sample of cells from each well was stained with PI (10 µg/ml) and viable cells (PI -) were counted with a flow cytometer (Millipore Guava

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“…Additionally, a pre-clinical report on the role of glutamine addiction in ccRCC further supports the possibility of therapeutically targeting this axis in kidney cancer [106]. Aboud, et al demonstrate that ccRCC tumors grown orthotopically show increased uptake of 18 F-(2 S ,4 R )4-fluoroglutamine relative to adjacent healthy kidney tissue and are sensitive to glutaminase inhibition by CB-839.…”

Section: Therapeutic Strategies For Ccrccmentioning

confidence: 98%

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez

Simon

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

117

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Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.

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Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

Cited by 92 publications

References 57 publications

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

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

Targeting glutamine metabolism and redox state for leukemia therapy

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

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