Dataset Information

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by ?-Catenin Mutations.

ABSTRACT: Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-?-catenin signaling. Activating ?-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between ?-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were ?-catenin-mutated liver tumors. Genetic disruption of ?-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in ?-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-?-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are ?-catenin mutated and GS positive.

SUBMITTER: Adebayo Michael AO

PROVIDER: S-EPMC6506359 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations.

Adebayo Michael Adeola O AO Ko Sungjin S Tao Junyan J Moghe Akshata A Yang Hong H Xu Meng M Russell Jacquelyn O JO Pradhan-Sundd Tirthadipa T Liu Silvia S Singh Sucha S Poddar Minakshi M Monga Jayvir S JS Liu Pin P Oertel Michael M Ranganathan Sarangarajan S Singhi Aatur A Rebouissou Sandra S Zucman-Rossi Jessica J Ribback Silvia S Calvisi Diego D Qvartskhava Natalia N Görg Boris B Häussinger Dieter D Chen Xin X Monga Satdarshan P SP

Cell metabolism 20190131 5

Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), an ...[more]

PMID: 30713111

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Project description:BackgroundAutoimmune hepatitis (AIH) is mediated by a cascade of T cell-mediated events directed at liver cells and persistent inflammation within the liver can eventually result in liver cirrhosis. Targeting glutamine metabolism has an impact on T cell activation and differentiation. However, the effect of glutamine metabolism blocking upon AIH remains unknown. We use glutaminase antagonist 6-diazo-5-oxo-L-norleucine (DON) for in vitro assays and its prodrug 2-(2-amino-4-methylpentanamido)-DON (JHU083) for in vivo assays to investigate the potential therapeutic effect and molecular mechanism of glutamine metabolism blocking in an AIH murine model.MethodsAIH mice were treated with JHU083 or vehicle before concanavalin A (ConA) administration, and disease severity was examined. Then activation and differentiation [including Th1/Th17 cells and cytotoxic T lymphocytes (CTL)] of T cells from Vehicle-WT, JHU083-AIH and Vehicle-AIH mice were tested. Furthermore, in vitro T cell activation and differentiation were measured using separated splenocytes stimulated with ConA with or without DON. The activation and differentiation of T cells were tested using flow cytometry, qRT-PCR and ELISA. Phosphorylation level of mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (P70S6K) were examined by western blotting.ResultsJHU083 and DON significantly suppressed the activation of T cells and inhibited the differentiation of Th1/Th17 cells and CTL in vivo and in vitro. Besides, we demonstrated that glutamine metabolism blocking inhibited T cells activation and differentiation through decreasing the mRNA expression of amino acid transporter solute carrier family 7 member 5 (SLC7A5) and mitigating the activation of mTOR signaling.ConclusionsWe proved that targeting glutamine metabolism represents a potential new treatment strategy for patients with AIH and other T cell-mediated disease. Mechanistically, we demonstrated that glutamine metabolism blocking inhibits T cells activation and suppresses the differentiation of Th1/Th17 cells and CTL.

Project description:Background/objectivesPrevious research has shown maternal betaine supplementation alleviates fetal-derived hepatic steatosis. Therefore, this study examined the anti-inflammatory effect of maternal betaine intake in offspring mice and its mechanism.Materials/methodsFemale C57BL/6J mice and their offspring were randomly divided into 3 groups according to the treatment received during gestation and lactation: control diet (CD), fatty liver disease (FLD), and fatty liver disease + 1% betaine (FLD-BET). The FLD group was given a high-fat diet and streptozotocin (HFD + STZ), and the FLD-BET group was treated with HFD + STZ + 1% betaine. After weaning, the offspring mice were given a normal diet for 5 weeks and then dissected to measure the relevant indexes.ResultsCompared to the CD group, the offspring mice in the FLD group revealed obvious hepatic steatosis and increased serum levels of alanine aminotransferase, interleukin (IL)-6, and tumor necrosis factor (TNF)-α; maternal betaine supplementation reversed these changes. The hepatic mRNA expression levels of IL-6, IL-18, and Caspase-1 were significantly higher in the FLD group than in the CD group. Maternal betaine supplementation reduced the expression of IL-1β, IL-6, IL-18, and apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC). Maternal betaine supplementation also reversed the increasing protein expressions of nitric oxide dioxygenase-like receptor family pyrin domain containing 3 (NLRP3), ASC, Caspase-1, IL-1β, and IL-18 in offspring mice exposed to HFD + STZ. Maternal betaine supplementation decreased the homocysteine (Hcy) and s-adenosine homocysteine (SAH) levels significantly in the livers. Furthermore, the hepatic Hcy concentrations showed significant inverse relationships with the mRNA expression of TNF-α, NLRP3, ASC, and IL-18. The hepatic SAH concentration was inversely associated with the IL-1β mRNA expression.ConclusionsThe lipotropic and anti-inflammatory effect of maternal betaine supplementation may be associated with the inhibition of NLRP3 inflammasome in the livers of the offspring mice.

Dataset Information

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by ?-Catenin Mutations.

Publications

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations.

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