Journal Article

ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma

Zhang, Ze, Huang, Yuting, Jin, Rui, Shuai, Yanjie, Wang, Xudong, Luo, Jingtao, Liu, Ruoyan

2020

Overview

Background 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. Methods The 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. Results We 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. Conclusions In 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1059/602 / 631/67/1536 / 631/67/2327 / Amino Acid Transport System ASC - genetics / Amino Acid Transport System ASC - metabolism / Amino acids / Animals / Antineoplastic Agents, Immunological - pharmacology / Antineoplastic Agents, Immunological - therapeutic use / Apoptosis / Apoptosis - drug effects / Autophagy / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Survival - drug effects / Cetuximab - pharmacology / Cetuximab - therapeutic use / Disease Progression / Drug Resistance / Epidemiology / Female / Glutamine / Glutamine - metabolism / Glutathione / Head & neck cancer / Head and Neck Neoplasms - drug therapy / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - pathology / Humans / Immunofluorescence / Immunohistochemistry / Intracellular / Mechanistic Target of Rapamycin Complex 1 - metabolism / Metabolism / Mice / Mice, Nude / Minor Histocompatibility Antigens - genetics / Minor Histocompatibility Antigens - metabolism / Molecular Medicine / Monoclonal antibodies / Oncology / Oxidative stress / Oxidative Stress - drug effects / Phagocytosis / Signal Transduction - drug effects / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - drug therapy / Squamous Cell Carcinoma of Head and Neck - metabolism / Squamous Cell Carcinoma of Head and Neck - pathology / Targeted cancer therapy / Transfection / Tumor Burden - drug effects / Tumorigenesis / Xenograft Model Antitumor Assays