Cancer Metabolism

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

Abstract

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.

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Acknowledgements

We thank the TCGA project for its valuable contributions to HNSCC research.

Author information

Z.Z, X.W, J.L contributed to the study design. Z.Z, R.L, Y.S, Y.H, J.L contributed to data collection. Z.Z, R.L, Y.S contributed to the data analysis. Z.Z, R.L, Y.H, R.J contributed to writing of the draft version of the manuscript. Z.Z, R.L, Y.S, Y.H, R.J, X.W, J.L have read, revised and have approved the final version of the manuscript being submitted for peer review.

Correspondence to Jingtao Luo.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted with approval from the ethics committee of Tianjin Cancer Hospital, and informed consent was obtained for experimentation. This study was performed in accordance to the Declaration of Helsinki.

Funding

This study was supported by the Natural Science Foundation of China (no. 81702698 and no. 81902757) and a grant from the Starting Foundation of MD/PhD and Introduced Talent issued by Tianjin Medical University Cancer Institute and Hospital. (no. B1602, B1720 and B1716).

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The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Zhang, Z., Liu, R., Shuai, Y. et al. ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma. Br J Cancer 122, 82–93 (2020). https://doi.org/10.1038/s41416-019-0637-9

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