Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation

Kates, Lance; Durinck, Steffen; Patel, Nisha; Stawiski, Eric; Kljavin, Noelyn M.; Foreman, Oded; Sipos, Bence; Solloway, Mark J.; Allan, Bernard B.; Peterson, Andrew S.

doi:10.1016/j.xcrm.2020.100058

Cited by 10 publications

(9 citation statements)

References 32 publications

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“…Single-cell transcriptomic profiling has shown SLC38A5 as a characteristic gene for the progenitors of glucagon-secreting α-cells [ 88 ]. Amino acid delivery via this transporter drives α-cell hyperplasia [ 89 , 90 ], and the elevation of amino acids in blood induces a subpopulation of α-cells to form pancreatic neuroendocrine tumors [ 91 ]. Interestingly, similar to SLC6A14, the expression of SLC38A5 is also under the control of the Wnt signaling pathway [ 92 , 93 , 94 ], thus suggesting a probable connection between this transporter and cancer.…”

Section: Upregulation Of Slc6a14 and Slc38a5 In Cancer Cells And Smentioning

confidence: 99%

SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

et al. 2021

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The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine–glycine–one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine–glycine–one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl− -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.

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Section: Upregulation Of Slc6a14 and Slc38a5 In Cancer Cells And Smentioning

confidence: 99%

SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

et al. 2021

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“…Once the GCGR is impaired, the glucagon-GCGR pathway is disrupted, which increases glucagon demand due to compensatory mechanisms. In response to the glucagon demand, α cells stimulated by factor/factors originating from the liver, such as amino acids, cause α-cell hyperplasia through proliferation ( 15 , 16 , 17 , 18 , 23 , 42 , 43 ). At the same time, the existing α cells also upregulate the glucagon mRNA and protein levels to meet the increased glucagon demand (this study).…”

Section: Discussionmentioning

confidence: 99%

Disruption of the glucagon receptor increases glucagon expression beyond α-cell hyperplasia in zebrafish

Kang¹,

Zheng²,

Jia³

et al. 2022

Journal of Biological Chemistry

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“…There are also other Gln transporters, including SLC6A14 and SLC38A5, reported to be upregulated in various tumor types (for SLC6A14: cervical cancer [71], colorectal cancer [72], estrogen-receptor-positive breast cancer [73], and pancreatic cancer [68]; for SLC38A5: TNBC [69] and pancreatic cancer [70]) and contributing to the overall Gln pool, which further highlights the importance of this nutrient in cancer cell metabolism. Furthermore, enhanced expression of SLC38A5 was shown to promote glutamine dependence and oxidative stress resistance in breast cancer [107].…”

Section: Glutamine Synthesis Glulmentioning

confidence: 95%

“…Breast cancer (TNBC) Clinical, in vitro, and in vivo [69] Pancreatic cancer Clinical and in vivo [70] Increased glutamine/arginine transport SLC6A14…”

Section: Slc38a5mentioning

confidence: 99%

Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap

Halama

Suhre

2022

Cancers

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Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.

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Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation

Cited by 10 publications

References 32 publications

SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

Disruption of the glucagon receptor increases glucagon expression beyond α-cell hyperplasia in zebrafish

Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap

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