Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers

Okazaki, Arimichi; Gameiro, Paulo A.; Christodoulou, Danos C.; Laviollette, Laura; Schneider, Meike; Cháves, Frances; Stemmer‐Rachamimov, Anat; Yazinski, Stephanie A.; Lee, Richard; Stephanopoulos, Gregory; Zou, Lee; Iliopoulos, Othon

doi:10.1172/jci87800

Cited by 83 publications

(85 citation statements)

References 59 publications

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“…However, we found that HIF1a attenuates later steps in the glutamine reductive carboxylation pathway by suppressing key players of this pathway involved in cytosolic aspartate generation, such as GOT1. It was recently shown that glutamine reductive carboxylation can contribute to aspartate generation in some VHL-deficient tumor cells (Okazaki et al, 2017). However, our data show not only that the glutamine reductive pathway does not compensate for the diminished aspartate generation through glutamine oxidation upon HIF1a activation, but that HIF1a actively limits aspartate biosynthesis through this reductive pathway involving suppression of cytosolic GOT1.…”

Section: Discussioncontrasting

confidence: 62%

HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

et al. 2019

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Graphical Abstract Highlights d HIF1a reduces intracellular aspartate levels d HIF1a impairs oxidative and reductive aspartate biosynthesis d The aspartate-generating GOT1 and GOT2 enzymes are repressed by HIF1a d Aspartate supplementation counteracts the antiproliferative influence of HIF1a In Brief Melé ndez-Rodríguez et al. show that HIF1a impairs oxidative and reductive aspartate biogenesis, which consequently drives HIF1a-dependent suppression of tumor cell proliferation. Mechanistically, HIF1a represses the aspartate-producing enzymes GOT1 and GOT2 in several biological settings, including human VHL-deficient renal cell carcinoma, in which HIF1a can act as a tumor suppressor.

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Section: Discussioncontrasting

confidence: 62%

HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

et al. 2019

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“…For example, GLS inhibition increases radiotherapy response in lung tumour xenografts 56 and synergy with poly(ADP-ribose) polymerase (PARP) inhibition was investigated in renal carcinoma cells, where GLS inhibitors led to nucleoside depletion and DNA replication stress. Combination of GLS1 inhibitors with PARP inhibitors (PARP i ) suppressed cell growth 57 . Collectively, these findings emphasize GLS' role in nucleotide synthesis, where inhibition leads to DNA damage and replication arrest.…”

Section: Discussionmentioning

confidence: 99%

Targeting glutamine metabolism slows soft tissue sarcoma growth

et al. 2020

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Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.

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“…Gls1 inhibitors have been considered for the treatment of various cancers in mice , and some of them have entered clinical trials . In this study we showed that deficiency of Gls1 resulted in decreased EAE and that treatment with BPTES reduced disease activity in MRL/ lpr mice.…”

Section: Discussionmentioning

confidence: 58%

Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus‐like Disease in MRL/lpr Mice and Experimental Autoimmune Encephalomyelitis

Kono

Yoshida

Maeda

et al. 2019

Arthritis & Rheumatology

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Objective Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl sulfide (BPTES) suppresses Th17 development and ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms. Methods MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17‐polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional‐knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia‐inducible factor 1α (HIF‐1α) was examined by Western blotting. Results Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17‐dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional‐knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF‐1α protein, which induces glycolysis. Conclusion We demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17‐related autoimmune diseases. Mechanistically, we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing HIF‐1α protein in Th17 cells.

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Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers

Cited by 83 publications

References 59 publications

HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

Targeting glutamine metabolism slows soft tissue sarcoma growth

Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus‐like Disease in MRL/lpr Mice and Experimental Autoimmune Encephalomyelitis

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