Hopefully devoted to Q: targeting glutamine addiction in cancer

Still, Emma R; Yuneva, Mariia

doi:10.1038/bjc.2017.113

Cited by 98 publications

(96 citation statements)

References 58 publications

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“…Our data suggests that the intrinsic ability of GS-CHO cells to synthesize Gln effectively protects cells from an amino acid starvation response. The protective effect of Gln derives from its multiple roles in the cell as a metabolic fuel for mitochondrial anaplerosis, protein, nucleotide and fatty acid synthesis, reactive oxygen species homeostasis (Still & Yuneva, 2017), and Gln has the ability to regulate gene expression in a variety of cellular processes (Brasse-Lagnel, Lavoinne, & Husson, 2009;Curi et al, 2007). More specifically, Gln has been shown to restore or stimulate mTORC1 (a central regulator of cell growth) activity during amino acid starvation (Chiu et al, 2012;Tan, Sim, & Long, 2017) and also via glutaminolysis (Durán et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Control of amino acid transport into Chinese hamster ovary cells

Geoghegan

Arnall

Hatton³

et al. 2018

Biotech & Bioengineering

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Amino acid transporters (AATs) represent a key interface between the cell and its environment, critical for all cellular processes: Energy generation, redox control, and synthesis of cell and product biomass. However, very little is known about the activity of different functional classes of AATs in Chinese hamster ovary (CHO) cells, how they support cell growth and productivity, and the potential for engineering their activity and/or the composition of amino acids in growth media to improve CHO cell performance in vitro. In this study, we have comparatively characterized AAT expression in untransfected and monoclonal antibody (MAb)‐producing CHO cells using transcriptome analysis by RNA‐seq, and mechanistically dissected AAT function using a variety of transporter‐specific chemical inhibitors, comparing their effect on cell proliferation, recombinant protein production, and amino acid transport. Of a possible 56 mammalian plasma membrane AATs, 16 AAT messenger RNAs (mRNAs) were relatively abundant across all CHO cell populations. Of these, a subset of nine AAT mRNAs were more abundant in CHO cells engineered to produce a recombinant MAb. Together, upregulated AATs provide additional supply of specific amino acids overrepresented in MAb biomass compared to CHO host cell biomass, enable transport of synthetic substrates for glutathione synthesis, facilitate transport of essential amino acids to maintain active protein synthesis, and provide amino acid substrates for coordinated antiport systems to maintain supplies of proteinogenic and essential amino acids.

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Section: Resultsmentioning

confidence: 99%

Control of amino acid transport into Chinese hamster ovary cells

Geoghegan

Arnall

Hatton³

et al. 2018

Biotech & Bioengineering

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“…Amino acids have also been shown to be significant in development of cancer, with evidence for glutamine, serine, and glycine as necessary nutrients in rapidly dividing cancer cells. While an increase in leucine, isoleucine, and valine has been shown to be associated with early stage development of pancreatic adenocarcinoma, and depletion of circulating aspartate is associated with breast cancer .…”

Section: Cancer Biomarkers: the Role Of Metabolomicsmentioning

confidence: 99%

Discovery and Validation of Clinical Biomarkers of Cancer: A Review Combining Metabolomics and Proteomics

Srivastava

Creek

2018

Proteomics

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Early detection and diagnosis of cancer can allow timely medical intervention, which greatly improves chances of survival and enhances quality of life. Biomarkers play an important role in assisting clinicians and health care providers in cancer diagnosis and treatment follow‐up. In spite of years of research and the discovery of thousands of candidate cancer biomarkers, only a few have transitioned to routine usage in the clinic. This review highlights advances in proteomics technologies that have enabled high rates of discovery of candidate cancer biomarkers and evaluates integration with other omics technologies to improve their progress through to validation and clinical translation. Furthermore, it gauges the role of metabolomics technology in cancer biomarker research and assesses it as a complementary tool in aiding cancer biomarker discovery and validation.

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“…The genetic reprogramming of some cancer types to make use of glutamine as an alternative nutrient source includes increased expression of proteins that act as transporters of amino acids, such as SLC1A5 (ASTC2), or the upregulation of enzymes that catalyze the metabolism of glutamine, for example, glutaminase . Proliferating cancer cells use glutamine as a nitrogen donor for the synthesis of nucleotide precursors, and following the conversion to glutamate, the generation of the amino acids alanine and aspartate . The conversion to glutamate also enables cells to use glutamine as a carbon source for the production of α‐ketoglutarate through the activity of glutamine dehydrogenase or an aminotransferase, including PSAT1 .…”

Section: Introductionmentioning

confidence: 99%

“…15 Proliferating cancer cells use glutamine as a nitrogen donor for the synthesis of nucleotide precursors, and following the conversion to glutamate, the generation of the amino acids alanine and aspartate. 4,16,17 The conversion to glutamate also enables cells to use glutamine as a carbon source for the production of α-ketoglutarate through the activity of glutamine dehydrogenase or an aminotransferase, including PSAT1. 4,16,17 Strategies to exploit the dependence of some tumor types on glutamine that are under development include the use of glutamine transport or enzyme inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…4,16,17 The conversion to glutamate also enables cells to use glutamine as a carbon source for the production of α-ketoglutarate through the activity of glutamine dehydrogenase or an aminotransferase, including PSAT1. 4,16,17 Strategies to exploit the dependence of some tumor types on glutamine that are under development include the use of glutamine transport or enzyme inhibitors. [18][19][20] Ewing sarcoma (EWS), a soft tissue and bone tumor, primarily occurs in adolescents and young adults.…”

Section: Introductionmentioning

confidence: 99%

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EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis

Sen

Cross

Lorenzi

et al. 2018

Molecular Carcinogenesis

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Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS‐FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS‐FLI1 binding and activation or repression of transcription. Here, we demonstrate that EWS‐FLI1 positively regulates the expression of proteins required for serine‐glycine biosynthesis and uptake of the alternative nutrient source glutamine. Specifically, we show that EWS‐FLI1 activates expression of PHGDH, PSAT1, PSPH, and SHMT2. Using cell‐based studies, we also establish that EWS cells are dependent on glutamine for cell survival and that EWS‐FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and two enzymes involved in the one‐carbon cycle, MTHFD2 and MTHFD1L. Inhibition of serine‐glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species, DNA damage, and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned genes we identified as regulated by EWS‐FLI1 exhibit increased expression compared with normal tissues. Furthermore, retrospective analysis of an independent data set generated a significant stratification of the overall survival of EWS patients into low‐ and high‐risk groups based on the expression of PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, and MTHFD1L. In summary, our study demonstrates that EWS‐FLI1 reprograms the metabolism of EWS cells and that serine‐glycine metabolism or glutamine uptake are potential targetable vulnerabilities in this tumor type.

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Hopefully devoted to Q: targeting glutamine addiction in cancer

Cited by 98 publications

References 58 publications

Control of amino acid transport into Chinese hamster ovary cells

Control of amino acid transport into Chinese hamster ovary cells

Discovery and Validation of Clinical Biomarkers of Cancer: A Review Combining Metabolomics and Proteomics

EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis

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