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

Hassanein, Mohamed; Hoeksema, Megan D.; Shiota, Masakazu; Qian, Jun; Harris, Bradford K.; Chen, Heidi; Clark, Jonathan E.; Alborn, William E.; Eisenberg, Rosana; Massion, Pierre P.

doi:10.1158/1078-0432.ccr-12-2334

Cited by 288 publications

(291 citation statements)

References 36 publications

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“…55 Finally, our data indicate that blocking Gln uptake could be, possibly in association with other approaches, a suitable target to inhibit MM cell growth as also reported for other hematologic malignancies. 23,24,27 In line with this hypothesis, we show that bortezomib increased the cytotoxic effect of E. chrysanthemi ASNase as previously reported for acute leukemia cells. 56 Others recently showed that CB-839 blocks MM growth and synergized with pomalidomide in a preclinical model, 57 and a phase 1 trial with CB-839 in patients with R-MM is currently under investigation.…”

Section: Discussionsupporting

confidence: 91%

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Bolzoni

Chiu

Accardi

et al. 2016

Blood

150

156

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Key Points• Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression.• Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138 1 cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138 1 cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138 1 cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM. (Blood. 2016;128(5):667-679)

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Section: Discussionsupporting

confidence: 91%

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Bolzoni

Chiu

Accardi

et al. 2016

Blood

150

156

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“…First, ASCT2, the Na + -dependent neutral amino acid transporter encoded by SLC1A5, is broadly expressed in lung cancer cell lines and accounts for a majority of glutamine transport in those cells (Figure 1). It has been shown that γ-L-glutamylp-nitroanilide (GPNA) inhibits this transporter and limits lung cancer cell growth (73). Additional interest in GPNA lies in its ability to enhance the uptake of drugs imported via the monocarboxylate transporter MCT1.…”

Section: Pharmacological Strategies To Inhibit Glutamine Metabolism Imentioning

confidence: 99%

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

Hensley¹,

Wasti²,

2013

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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. IntroductionIt has been nearly a century since the discovery that tumors display metabolic activities that distinguish them from differentiated, non-proliferating tissues and presumably contribute to their supraphysiological survival and growth (1). Interest in cancer metabolism was boosted by discoveries that oncogenes and tumor suppressors could regulate nutrient metabolism, and that mutations in some metabolic enzymes participate in the development of malignancy (2, 3). The persistent appeal of cancer metabolism as a line of investigation lies both in its ability to uncover fundamental aspects of malignancy and in the translational potential of exploiting cancer metabolism to improve the way we diagnose, monitor, and treat cancer. Furthermore, an improved understanding of how altered metabolism contributes to cancer has a high potential for synergy with translational efforts. For example, the demonstration that asparagine is a conditionally essential nutrient in rapidly growing cancer cells paved the way for L-asparaginase therapy in leukemia. Additionally, the avidity of some tumors for glucose uptake led to the development of 18 fluoro-2-deoxyglucose imaging by PET; this in turn stimulated hundreds of studies on the biological underpinnings of tumor glucose metabolism.There continue to be large gaps in understanding which metabolic pathways are altered in cancer, whether these alterations benefit the tumor in a substantive way, and how this information could be used in clinical oncology. In this Review, we consider glutamine, a highly versatile nutrient whose metabolism has implications for tumor cell biology, metabolic imaging, and perhaps novel therapeutics.

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“…Other research identified microenvironment-related pathways important for lung tumor growth and progression. These pathways included Rab27a (39), SLC1A5 (40), and vascular endothelial growth factor receptor (VEGFR)-2/epidermal growth factor receptor (EGFR) (41). In a recent perspective, Stathopoulos and Kalomenidis note and review the importance of tumor-host interactions in the formation of malignant pleural effusions (42).…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Update in Lung Cancer and Mesothelioma 2012

Powell

Halmos

Nana‐Sinkam

2013

Am J Respir Crit Care Med

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Lung cancer remains the number one cause of cancer-related death in the United States among both men and women. It is estimated that in 2013, there will be more than 200,000 new diagnoses of lung cancer and nearly 160,000 deaths (1). Despite the discovery and application of targeted therapies, the overall survival (OS) remains poor, with an overall 5-year survival approximating 16%. In addition, there are a growing number of cases among former smokers and never smokers. However, based on research advances in 2012, there is enthusiasm that improvements in early detection, coupled with tobacco cessation and the application of novel genetic and genomics technologies, will lead to improved outcomes. EPIDEMIOLOGYAlthough more than 85% of patients diagnosed with lung cancer will have smoked at some point in their lives, only 15 to 20% of smokers will develop lung cancer, thus suggesting the involvement of additional risk factors. Studies examining the roles of various exposures, including asbestos, welding, arsenic, and concomitant lung diseases, such as chronic obstructive pulmonary disease (COPD), tuberculosis, and pneumonia, as risk factors independent of tobacco consumption are ongoing (2, 3). A recent large epidemiological study in more than 2,000 incident cases of lung cancer cases and control subjects identified a 36% increase in lung cancer risk among welders and flame cutters. Interestingly, welding fumes were an independent risk factor for lung cancer (4). DisparitiesA recent examination of multiple registries confirmed that African Americans have the highest incidence of lung cancer (73/100,000) (5) and have a decreased OS and lower rates of surgical resection. Factors contributing to the disparities in lung cancer include inequities in access to health care, differing perceptions regarding early detection, smoking cessation and treatment, and variation in susceptibilities to the effects of cigarette smoke (6, 7). Conversely, the incidence rates for lung cancer among Hispanic men are much lower, and OS is better than in non-Hispanic whites. The explanations for these differences include a combination of decreased smoking rates among Hispanics, potential genetic variants (8), and histological distribution. Saeed and colleagues conducted a systematic analysis of the SEER database and determined that Hispanics had a higher rate of less aggressive histological subtypes of lung cancer (adenocarcinoma in situ and lepidic predominant adenocarcinoma) (9). Investigation of these areas should help to narrow the lung cancer outcomes gap that exists between ethnic groups.

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

Cited by 288 publications

References 36 publications

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

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

Update in Lung Cancer and Mesothelioma 2012

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