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.

Analysis of TCGA data of differentially expressed EMT‑related genes and miRNAs across various malignancies to identify potential biomarkers

“…Moreover, miR-137 exhibits crucial developmental roles in neuronal differentiation (57). In addition, miR-137, by modulating SLC1A5-dependent glutamine uptake, is involved in the progression of head and neck squamous cell carcinoma (58,59). The significant role of miR-137 in the progression, diagnosis and prognosis of hepatocellular carcinoma has also been documented (60).…”

Amino Acid Transporters on the Guard of Cell Genome and Epigenome

“…While five members of this family (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7) function as high-affinity Glu transporters, the remaining two (SLC1A4 and SLC1A5) work as neutral amino acid transporters [ 25 ]. In general, members of this family are essential for activation of the mTOR pathway to maintain cell growth and proliferation as reviewed in [ 26 ], and for coping with oxidative stress due to their contribution to the synthesis of GSH [ 27 , 28 , 29 ].…”

“…V-9032 specifically and effectively targets SLC1A5 and thus leads to the attenuation of proliferation and growth of cancer cells as well as elevation of oxidative stress and cell death, contributing to anti-tumor responses both in vivo and in vitro [ 163 ]. Furthermore, either short hairpin RNA (shRNA) or miR-137-mediated silencing of SLC1A5 and pharmacological inhibition of SLC38A2 and SLC1A5 by V-9302 abolish intracellular Gln levels as well as Gln metabolism that eventually affects GSH production [ 29 ]. Overall, these effects lead to an increase in apoptosis, autophagy, and oxidative stress and suppression of the mTORC1 signaling and cell proliferation in HNSCC, further boosting tumor cell sensitivity to cetuximab treatment [ 29 ].…”

Amino Acid Transporters as Potential Therapeutic Targets in Thyroid Cancer

“…ASCT2, an Na + -dependent neutral amino acid transporter encoded by SLC1A5 , is predominantly localized at the cell membrane [ 35 ] and mediates the exchange of amino acid substrates, particularly mediating rapid glutamine uptake in proliferating cancer cells [ 36 ]. ASCT2 upregulation worsens the prognosis of HNSCC, clear-cell renal-cell carcinoma, gastric cancer, triple-negative breast cancer, ovarian cancer, and other cancers [ 37 , 38 ]. Kim et al [ 39 ] (2016) reported ASCT2 upregulation in MTC originating from parafollicular cells but not in other TCs of follicular origin, including PTC, FTC, poorly differentiated carcinoma, and ATC.…”