mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT

Gu, Yuchao; Albuquerque, Claudio P.; Braas, Daniel; Zhang, Wei; Villa, Genaro R.; Bi, Junfeng; Ikegami, Shiro; Masui, Kenta; Gini, Beatrice; Yang, Huijun; Gahman, Timothy C.; Shiau, Andrew K.; Cloughesy, Timothy F.; Christofk, Heather R.; Zhou, Huilin; Guan, Kun‐Liang; Mischel, Paul S.

doi:10.1016/j.molcel.2017.05.030

Cited by 155 publications

(163 citation statements)

References 59 publications

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“…Of note, post-translational regulation of xCT downstream of PI3K resulting in phosphorylation of Ser 26 and inhibition of Cys 2 uptake has been previously reported (42), and as such is consistent with the results presented here. Gu et al identified mTORC2 but not AKT as the kinase responsible for phosphorylation of xCT at Ser 26 in cells.…”

Section: Discussionsupporting

confidence: 94%

“…Gu et al identified mTORC2 but not AKT as the kinase responsible for phosphorylation of xCT at Ser 26 in cells. However, consistent with our data, they also showed that AKT can potentially phosphorylate xCT with in vitro kinase assays (42). The motif surrounding Ser 26 in xCT conforms only partially to both the mTOR (43, 44) and the AKT consensus motifs (45, 46), and the responsible kinase in vivo may therefore conceivably depend on distinct cellular contexts.…”

Section: Discussionsupporting

confidence: 91%

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Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT

et al. 2017

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The precursor homocysteine is metabolized either through the methionine cycle to produce methionine or through the transsulfuration pathway to synthesize cysteine. Alternatively, cysteine can be obtained through uptake of its oxidized form, cystine. Many cancer cells exhibit methionine dependency such that their proliferation is impaired in growth media in which methionine is replaced by homocysteine. Here, we showed that oncogenic PIK3CA and decreased expression of SLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells. Oncogenic PIK3CA was sufficient to confer methionine dependency to mammary epithelial cells, in part by decreasing cystine uptake through the transcriptional and posttranslational inhibition of xCT. Manipulation of xCT activity altered the proliferation of breast cancer cells in methionine-deficient, homocysteine-containing media, suggesting that it functionally contributed to methionine dependency. We propose that concurrent with decreased cystine uptake through xCT, PIK3CA mutant cells use homocysteine through the transsulfuration pathway to synthesize cysteine. Consequently, less homocysteine is available to produce methionine, contributing to methionine dependency. These results indicate that oncogenic PIK3CA alters methionine and cysteine utilization, in part by inhibiting xCT, to contribute to the methionine dependency phenotype in breast cancer cells.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT

et al. 2017

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“…mTORC2 requires either glucose or acetate for its activated status, and this mTORC2‐dependent glucose sensing mechanism would raise the possibility that under nutrient‐poor conditions, lower mTORC2 signaling could prefer glutamate efflux, cystine uptake, and glutathione synthesis to protect tumor cells from cellular stress at the expense of cell proliferation, the mechanism of which is based on the mTORC2‐dependent regulation of xCT systems (Fig. ) . The findings lead to the proposal that glucose and amino acid metabolism could interact through mTORC2 signaling, which enables cancer cells to promote their survival according to the microenvironment nutrient status …”

Section: Metabolic Reprogramming In Diffuse Gliomasmentioning

confidence: 99%

“…Additionally, combination of an xCT inhibitor, erastin, with Torin1 (dual mTOR kinase inhibitor) resulted in significant synergistic GBM cell death, indicating that increased xCT activity has a major contribution to glutathione synthesis and GBM cell survival upon pharmacological mTOR kinase inhibition (Fig. ) . Furthermore, nuclear factor‐κB‐mediated survival through mutant EGFR‐mTOR signaling could contribute to a novel resistance mechanism of GBM cells to chemotherapy as well as TKI treatment .…”

Section: Molecular Therapies Targeting Mutation‐dependent Metabolismmentioning

confidence: 99%

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Metabolic reprogramming in the pathogenesis of glioma: Update

et al. 2019

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Cancer is a genetic disease that is currently classified not only by its tissue and cell type of origin but increasingly by its molecular composition. Increasingly, tumor classification and subtyping is being performed based upon the oncogene gains, tumor suppressor losses, and associated epigenetic and transcriptional features. However, cancers, including brain tumors, are also characterized by profound alterations in cellular metabolism. At present, even though signature mutations in known metabolic enzymes are recognized as being important, the metabolic landscape of tumors is not currently incorporated into tumor diagnostic categories. Here we describe a set of recent discoveries on metabolic reprogramming driven by mutations in the genes for the isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways, which are the most commonly observed aberrations in diffuse gliomas. We highlight the importance of oncometabolites to dynamically shift the epigenetic landscape in IDH‐mutant gliomas, and c‐Myc and mechanistic target of rapamycin (mTOR) complexes in RTK‐mutated gliomas to adapt to the microenvironment through metabolic reprogramming. These signify the integration of the genetic mutations with metabolic reprogramming and epigenetic shifts in diffuse gliomas, shedding new light onto potential patient subsets, coupled with information to guide the development of new therapeutic opportunities against the deadly types of brain tumors.

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A Biomimetic Plasmonic Nanoreactor for Reliable Metabolite Detection

et al. 2020

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and the concomitant elevation of lactate in the interstitial fluids due to the enhanced glycolysis energy metabolism. [1] Accurate profiling of medically relevant metabolites in human body fluids provides molecular information for deep understanding of pathological mechanism at a more distal level than genomic analysis, and enables precise diagnosis and treatment of the underling diseases. [2] Till now, different advanced techniques, including magnetic resonance spectroscopy, [3] mass spectrometry, [4] and chromatography coupled mass spectroscopy, [5] have been developed to measure metabolites in vitro and in vivo. While useful, these techniques require sophisticated and expensive equipment, hampering their use in rapid point-ofcare clinical testing. By contrast, enzymebased bioassays, where the presence of analytes is optically or electrochemically detected through the highly specific and efficient enzymatic reaction, provide novel opportunities for detection metabolite biomarkers. [6] These approaches show enough figures of merits regarding device portability, speed, sample consumption and cost. However, the inherent instability of enzyme at elevated temperature, in circumstance containing digestive enzymes or chemical chelates, and when storing the enzyme long-term represents a longstanding yet largely unsolved challenge that leads to poor reproducibility and accuracy in enzyme-based metabolite analysis. [7] Reliable monitoring of metabolites in biofluids is critical for diagnosis, treatment, and long-term management of various diseases. Although widely used, existing enzymatic metabolite assays face challenges in clinical practice primarily due to the susceptibility of enzyme activity to external conditions and the low sensitivity of sensing strategies. Inspired by the micro/ nanoscale confined catalytic environment in living cells, the coencapsulation of oxidoreductase and metal nanoparticles within the nanopores of macroporous silica foams to fabricate all-in-one bio-nanoreactors is reported herein foruse in surface-enhanced Raman scattering (SERS)-based metabolic assays. The enhancement of catalytical activity and stability of enzyme against high temperatures, long-time storage or proteolytic agents are demonstrated. The nanoreactors recognize and catalyze oxidation of the metabolite, and provide ratiometric SERS response in the presence of the enzymatic by-product H 2 O 2 , enabling sensitive metabolite quantification in a "sample in and answer out" manner. The nanoreactor makes any oxidoreductase-responsible metabolite a candidate for quantitative SERS sensing, as shown for glucose and lactate. Glucose levels of patients with bacterial infection are accurately analyzed with only 20 µL of cerebrospinal fluids, indicating the potential application of the nanoreactor in vitro clinical testing.

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mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT

Cited by 155 publications

References 59 publications

Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT

Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT

Metabolic reprogramming in the pathogenesis of glioma: Update

A Biomimetic Plasmonic Nanoreactor for Reliable Metabolite Detection

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