Abstract
BackgroundGlutamine is an abundant and versatile nutrient in cancer cells. Head and neck squamous cell carcinoma (HNSCC) was reported to be dependent on mainly glucose, not glutamine, for producing the energy required for survival and proliferation.MethodsThe roles of ASCT2 (SLC1A5) and associated glutamine metabolism were determined by the MTT, colony formation, glutamine uptake, intracellular glutathione, ROS detection, immunofluorescence, immunohistochemistry, and apoptosis enzyme-linked immunosorbent assays as well as animal studies.ResultsWe found that glutamine is also critical for HNSCC. In this study, ASCT2, an amino acid transporter responsible for glutamine transport, in addition to LAT1 and GLS, is overexpressed in HNSCC and associated with poor survival. Using both in vivo and in vitro models, we found that knocking down ASCT2 by shRNAs or miR-137 or the combination of silencing ASCT2 and pharmacologically inhibiting SNAT2 via a small-molecule antagonist called V-9302 significantly suppressed intracellular glutamine levels and downstream glutamine metabolism, including glutathione production; these effects attenuated growth and proliferation, increased apoptosis and autophagy, and increased oxidative stress and mTORC1 pathway suppression in HNSCC. Additionally, silencing ASCT2 improved the response to cetuximab in HNSCC.ConclusionsIn summary, ASCT2-dependent glutamine uptake and subsequent glutamine metabolism are essential for HNSCC tumorigenesis, and the combination of glutamine uptake inhibitors and cetuximab presents a promising strategy for improving the outcomes of HNSCC patients.
Highlights
Glutamine is an abundant and versatile nutrient in cancer cells
ASCT2, LAT1 and GLS expression was increased in Head and neck squamous cell carcinoma (HNSCC) and inversely associated with patient survival To investigate the role of glutamine metabolism in HNSCC, we first conducted an analysis evaluating the prognostic significance of two amino acid transporters, ASCT2 and L-type amino acid transporter 1 (LAT1), and two glutaminases, GLS and GLS2
As membrane transporters of amino acids, ASCT2 is the transporter for glutamine uptake, and LAT1 exchanges intracellular glutamine with other extracellular amino acids, such as leucine
Summary
Glutamine is an abundant and versatile nutrient in cancer cells. Head and neck squamous cell carcinoma (HNSCC) was reported to be dependent on mainly glucose, not glutamine, for producing the energy required for survival and proliferation. Aberrant metabolism and metabolic reprogramming represent malignant tumour hallmarks that are required to sustain the high rate of proliferation of cancer cells, which have to compete for limited fuel in a crowded, nutrient-deprived microenvironment.[1,2] Glutamine, an abundant and versatile nutrient, has received substantial attention, second only to glucose, for its important role in energy generation, amino acid production, nucleotide biosynthesis, redox homeostasis, and autophagy and signalling regulation in cancer cells.[3,4,5] Glutamine serves as a critical source of carbon and nitrogen for macromolecular synthesis and provides α-ketoglutarate (α-KG) for the tricarboxylic acid (TCA) cycle and suppresses reactive oxygen species (ROS) levels through glutathione production These characteristics make targeting glutamine metabolism pharmacologically an appealing way to explore new clinical strategies for treating cancer.
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