Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine

Zhang, Ji; Pavlova, Natalya N.; Thompson, Craig B.

doi:10.15252/embj.201696151

Cited by 501 publications

(485 citation statements)

References 135 publications

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“…Glutamine is one of the major metabolites required by proliferating cells for protein synthesis, as well as being an important nitrogen and carbon source for nucleotide synthesis (1). To investigate the effect of SNX27 KO on cellular homeostasis, cell proliferation rates were firstly measured in the presence of the complete DMEM medium containing glutamine.…”

Section: Altered Cell Cycle Progression Upon Snx27 Knockoutmentioning

confidence: 99%

“…Glutamine is a major energy source utilized by mammalian cells to maintain cellular homeostasis and growth (1). Several subsets of solute carrier (SLC) protein families have been identified as glutamine transporters, regulating uptake of glutamine from the extracellular environment into cells, including SLC1A5, also known as the Alanine, Serine, Cysteine-preferring Transporter 2 (ASCT2; SLC1A5) (2).…”

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confidence: 99%

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Sorting nexin 27 (SNX27) regulates the trafficking and activity of the glutamine transporter ASCT2

Yang

Follett

Kerr

et al. 2018

Journal of Biological Chemistry

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The Alanine, Serine, Cysteine-preferring Transporter 2 (ASCT2; SLC1A5) is responsible for the uptake of glutamine into cells, a major source of cellular energy and a key regulator of mammalian Target of Rapamycin (mTOR) activation. Furthermore, ASCT2 expression has reported in several human cancers making it a potential target for both diagnostic and therapeutic purposes. Here we identify ASCT2 as a membrane trafficked cargo molecule, sorted through a direct interaction with the PDZ domain of Sorting Nexin 27 (SNX27). Using both membrane fractionation and subcellular localisation approaches we demonstrate that the majority of ASCT2 resides at the plasma membrane. This is significantly reduced within CrispR-mediated SNX27 Knock-Out (KO) cell lines, as it is missorted into the lysosomal degradation pathway. The reduction of ASCT2 levels in SNX27 KO cells leads to a decreased glutamine uptake, which in turn inhibits cellular proliferation. SNX27 KO cells also present impaired activation of mTOR complex 1 (mTORC1) pathway and enhanced autophagy. Taken together, our data reveals a role for SNX27 in glutamine uptake and amino acidstimulated mTORC1 activation via the modulation of ASCT2 intracellular trafficking.

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Section: Altered Cell Cycle Progression Upon Snx27 Knockoutmentioning

confidence: 99%

mentioning

confidence: 99%

Sorting nexin 27 (SNX27) regulates the trafficking and activity of the glutamine transporter ASCT2

Yang

Follett

Kerr

et al. 2018

Journal of Biological Chemistry

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“…This process generates NADH as well as metabolites required for de novo synthesis of macromolecules and lipids. Glutamine is also an important source of reduced nitrogen required for the biosynthesis of both purines and pyrimidines [64, 65]. …”

Section: Introductionmentioning

confidence: 99%

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

Biancur

Kimmelman

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

107

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Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that is highly refractory to the current standards of care. The difficulty in treating this disease is due to a number of different factors, including altered metabolism. In PDA, the metabolic rewiring favors anabolic reactions which supply the cancer cell with necessary cellular building blocks for unconstrained growth. Furthermore, PDA cells display high levels of basal autophagy and macropinocytosis. KRAS is the driving oncogene in PDA and many of the metabolic changes are downstream of its activation. Together, these unique pathways for nutrient utilization and acquisition result in metabolic plasticity enabling cells to rapidly adapt to nutrient and oxygen fluctuations. This remarkable adaptability has been implicated as a cause of the intense therapeutic resistance. In this review, we discuss metabolic pathways in PDA tumors and highlight how they contribute to the pathogenesis and treatment of the disease.

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“…Initiated by Warburg's seminal work, discoveries in metabolic alterations in cancer continue to raise tremendous interest . Glutamine dependency, the abnormally increased glutaminolysis, has been widely recognized as an important hallmark of cancer metabolism . Glutamine, the most abundant free amino acid, plays a key role in cancer progression, including maintenance of carboxylic acid pools in the tricarboxylic acid cycle, sustaining cellular oxidative phosphorylation, and synthesis of the nonessential amino acids, purine, pyrimidines, and fatty acids .…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma‐specific survival

Chen

Liu

et al. 2019

Molecular Carcinogenesis

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Glutamine dependence is a unique metabolic defect seen in cutaneous melanoma (CM), directly influencing the treatment and prognosis. Here, we investigated the associations between 6025 common single‐nucleotide polymorphisms (SNPs) in 77 glutamine metabolic pathway genes with CM‐specific survival (CMSS) using genotyping datasets from two published genome‐wide association studies (GWASs). In the single‐locus analysis, 76 SNPs were found to be significantly associated with CMSS (P < .050, false‐positive report probability < 0.2 and Bayesian false discovery probability < 0.8) in the discovery dataset, of which seven SNPs were replicated in the validation dataset and three SNPs (HAL rs17676826T > C, LGSN rs12663017T > A, and NOXRED1 rs8012548A > G) independently predicted CMSS, with an effect‐allele attributed adjusted hazards ratio of 1.52 (95% confidence interval = 1.19‐1.93) and P < .001, 0.68 (0.54‐0.87) and P = .002 and 0.62 (0.46‐0.83) and P = .002, respectively. The model including the number of unfavorable genotypes (NUGs) of these three SNPs and covariates improved the five‐year CMSS prediction (P = .012) than the one with other covariates only. Further expression quantitative trait loci (eQTL) analysis found that the LGSN rs12663017 A allele was significantly associated with increased messenger RNA (mRNA) expression levels (P = 8.89 × 10 −11) in lymphoblastoid cell lines of the 1000 Genomes Project database. In the analysis of the genotype tissue expression (GTEx) project datasets, HAL rs17676826 C and NOXRED1 rs8012548 G alleles were significantly associated with their mRNA expression levels in sun‐exposed skin of the lower leg (P = 6.62 × 10−6 and 1.37 × 10−7, respectively) and in sun‐not‐exposed suprapubic skin (P < .001 and 1.43 × 10−8, respectively). Taken together, these genetic variants of glutamine‐metabolic pathway genes may be promising predictors of survival in patients with CM.

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Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine

Cited by 501 publications

References 135 publications

Sorting nexin 27 (SNX27) regulates the trafficking and activity of the glutamine transporter ASCT2

Sorting nexin 27 (SNX27) regulates the trafficking and activity of the glutamine transporter ASCT2

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma‐specific survival

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