Glutamine is an abundant and versatile nutrient that participates in energy formation, redox homeostasis, macromolecular synthesis, and signaling in cancer cells. These characteristics make glutamine metabolism an appealing target for new clinical strategies to detect, monitor, and treat cancer. Here we review the metabolic functions of glutamine as a super nutrient and the surprising roles of glutamine in supporting the biological hallmarks of malignancy. We also review recent efforts in imaging and therapeutics to exploit tumor cell glutamine dependence, discuss some of the challenges in this arena, and suggest a disease-focused paradigm to deploy these emerging approaches.

/pdf/glutamine-and-cancer-cell-biology-physiology-and-clinical-5gav80whfu.pdf

Glutamine and cancer: cell biology, physiology, and clinical opportunities.

Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

/pdf/slc-transporters-as-therapeutic-targets-emerging-tymmh6ta8e.pdf

SLC transporters as therapeutic targets: emerging opportunities

Glutamine is the most abundant circulating amino acid in blood and muscle and is critical for many fundamental cell functions in cancer cells, including synthesis of metabolites that maintain mitochondrial metabolism; generation of antioxidants to remove reactive oxygen species; synthesis of nonessential amino acids (NEAAs), purines, pyrimidines, and fatty acids for cellular replication; and activation of cell signaling. In light of the pleiotropic role of glutamine in cancer cells, a comprehensive understanding of glutamine metabolism is essential for the development of metabolic therapeutic strategies for targeting cancer cells. In this article, we review oncogene-, tumor suppressor–, and tumor microenvironment–mediated regulation of glutamine metabolism in cancer cells. We describe the mechanism of glutamine's regulation of tumor proliferation, metastasis, and global methylation. Furthermore, we highlight the therapeutic potential of glutamine metabolism and emphasize that clinical application of in vi...

Glutaminolysis: A Hallmark of Cancer Metabolism

Metabolic reprogramming is widely observed during cancer development to confer cancer cells the ability to survive and proliferate, even under the stressed, such as nutrient-limiting, conditions. It is famously known that cancer cells favor the “Warburg effect”, i.e., the enhanced glycolysis or aerobic glycolysis, even when the ambient oxygen supply is sufficient. In addition, deregulated anabolism/catabolism of fatty acids and amino acids, especially glutamine, serine and glycine, have been identified to function as metabolic regulators in supporting cancer cell growth. Furthermore, extensive crosstalks are being revealed between the deregulated metabolic network and cancer cell signaling. These exciting advancements have inspired new strategies for treating various malignancies by targeting cancer metabolism. Here we review recent findings related to the regulation of glucose, fatty acid and amino acid metabolism, their crosstalk, and relevant cancer therapy strategy.

Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression

Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation.

/pdf/asct2-slc1a5-controls-glutamine-uptake-and-tumour-growth-in-58ro22f3l7.pdf

ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

Purpose: We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non–small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival. Experimental Design: To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting ( N = 98) and in cell lines ( N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines. Results: Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na + -dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling. Conclusions: These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells9 metabolism, growth, and survival. Clin Cancer Res; 19(3); 560–70. ©2012 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/19/3/560.full.pdf

SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival

Quantitative analysis of protein biomarkers in plasma is typically done by ELISA, but this method is limited by the availability of high-quality antibodies An alternative approach is protein immunoprecipitation combined with multiple reaction monitoring mass spectrometry (IP-MRM) We compared IP-MRM to ELISA for the analysis of six colon cancer biomarker candidates (metalloproteinase inhibitor 1 (TIMP1), cartilage oligomeric matrix protein (COMP), thrombospondin-2 (THBS2), endoglin (ENG), mesothelin (MSLN) and matrix metalloproteinase-9 (MMP9)) in plasma from colon cancer patients and noncancer controls Proteins were analyzed by multiplex immunoprecipitation from plasma with the ELISA capture antibodies, further purified by SDS-PAGE, digested and analyzed by stable isotope dilution MRM IP-MRM provided linear responses (r = 0978–0995) between 10 and 640 ng/mL for the target proteins spiked into a “mock plasma” matrix consisting of 60 mg/mL bovine serum albumin Measurement variation (coefficient of va

https://pubs.acs.org/doi/pdf/10.1021/pr400877e

Comparison of Protein Immunoprecipitation-Multiple Reaction Monitoring with ELISA for Assay of Biomarker Candidates in Plasma

Biobank development and integration with clinical data from electronic medical record (EMR) databases have enabled recent strides in genomic research and personalized medicine. BioVU, Vanderbilt’s DNA biorepository linked to de-identified clinical EMRs, has proven fruitful in its capacity to extensively appeal to numerous areas of biomedical and clinical research, supporting the discovery of genotype-phenotype interactions. Expanding on experiences in BioVU creation and development, we have recently embarked on a parallel effort to collect plasma in addition to DNA from blood specimens leftover after routine clinical testing at Vanderbilt. This initiative offers expanded utility of BioVU by combining proteomic and metabolomic approaches with genomics and/or clinical outcomes, widening the breadth for potential research and subsequent future impact on clinical care. Here, we describe the considerations and components involved in implementing a plasma biobank program from a feasibility assessment through pilot sample collection.

https://www.mdpi.com/2075-4426/5/2/140/pdf

Phenotype-Driven Plasma Biobanking Strategies and Methods.

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SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival

Comparison of Protein Immunoprecipitation-Multiple Reaction Monitoring with ELISA for Assay of Biomarker Candidates in Plasma

Phenotype-Driven Plasma Biobanking Strategies and Methods.