A Role for p53 in the Adaptation to Glutamine Starvation through the Expression of SLC1A3

Tajan, Mylène; Höck, A.; Blagih, Julianna; Robertson, Neil; Labuschagne, Christiaan F.; Kruiswijk, Flore; Humpton, Timothy J.; Adams, Peter D.; Vousden, Karen H.

doi:10.1016/j.cmet.2018.07.005

Cited by 190 publications

(156 citation statements)

References 49 publications

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“…GLS deficiency, in contrast, allows glutamine uptake but leads to both glutamate and aspartate deficiencies and increased ROS. Glutamate and glutamine can be generated from other sources, such as aspartate, which can be p53 dependent and induce cell survival in glutamine-limiting conditions (Tajan et al, 2018). Given the interconnections of each metabolite in these pathways, it is likely that inhibition of this metabolic network leads to context-specific outcomes.…”

Section: Discussionmentioning

confidence: 99%

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Johnson

Wolf

Madden

et al. 2018

Cell

518

413

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SUMMARY Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Johnson

Wolf

Madden

et al. 2018

Cell

518

413

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“…In line with this, we observed that SLC1A3 expression could promote cancer cell metastasis, regardless of asparagine bioavailability (Figs D and EV5E). Even though recent studies mainly focused on the role of SLC1A3 in mediation of aspartate uptake (Alkan et al , ; Garcia‐Bermudez et al , ; Sullivan et al , ; Tajan et al , ), we could not exclude the role of glutamate, which could be converted to aspartate via oxidative or reductive carboxylation. This is supported by our findings that both aspartate and glutamate could rescue ASNase toxicity in SLC1A3 KO or negative cancer cells (Figs H and I).…”

Section: Discussionmentioning

confidence: 94%

“…SLC1A3 is mainly expressed in brain tissues (Fig EV1C), critical for the termination of excitatory neurotransmission (Kanai et al , ). Recent studies have highlighted the importance of SLC1A3‐mediated aspartate uptake for cancer cell proliferation under hypoxia and crosstalk between cancer cells and cancer‐associated fibroblasts in the tumor niche (Alkan et al , ; Garcia‐Bermudez et al , ; Sullivan et al , ; Tajan et al , ; Bertero et al , ). We also observed elevated SLC1A3 RNA levels in several tumor types from the TCGA database [especially kidney renal clear cell carcinoma (KIRC, P = 5.5 × 10 −30 ), kidney renal papillary cell carcinoma (KIRP, P = 2.1 × 10 −10 ), liver hepatocellular carcinoma (LIHC, P = 3.2 × 10 −10 ), and stomach adenocarcinoma (STAD, P = 6.1 × 10 −5 )] (Fig EV1D).…”

Section: Resultsmentioning

confidence: 99%

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

et al. 2019

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L‐asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

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“…Similar processes are likely to occur in other cancers. Indeed, recently EAAT1 has been implicated in supporting proliferation in several cancer cell lines representing solid cancers [62,63]. Both studies showed a main role for EAAT1 in the uptake of aspartate from the medium, especially under conditions of glutamine deprivation or asparaginase treatment.…”

Section: Discussionmentioning

confidence: 99%

T-ALL Proliferation Relies on Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides

Stanulović

Reed

Patani

et al. 2020

Preprint

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T-cell acute lymphoblastic leukaemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients relapse and die from the disease. To improve patient outcome new drugs are needed. With the aim to identify new therapeutic targets, we integrated transcriptomics and metabolomics data, including live-cell NMR-spectroscopy, of cell lines and patient samples. We found that T-ALL cells have limited energy availability, resulting in active AMPK-signalling and reduced autophagy. Despite this, mTOR kinase remains active and essential for glutamine-uptake that fuels rapid proliferation.Glutamine fuels aspartate synthesis and together they supply three nitrogen atoms in purines and all atoms but one carbon in pyrimidine rings. We show that EAAT1, a glutamateaspartate transporter normally only expressed in the CNS, is crucial for glutamine conversion to nucleotides and that T-ALL cell proliferation depends on EAAT1 function, identifying it as a target for T-ALL treatment. Finally, we performed an in silico screen and identified a novel EAAT1-specific allosteric inhibitor.

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A Role for p53 in the Adaptation to Glutamine Starvation through the Expression of SLC1A3

Cited by 190 publications

References 49 publications

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

T-ALL Proliferation Relies on Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides

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