Expression and roles of system L amino acid transporters in human embryonal carcinoma cells

Abstract

Background Testicular germ cell tumors (TGCTs) are the most common malignant cancer in young men. Although TGCTs are generally responsive to platinum‐based chemotherapy particularly cisplatin, acquired resistance in patients with metastasis still occurs resulting in poor prognosis. Specifically, differentiation of embryonal carcinoma (EC) cells, the stem cells of TGCTs, can lead to the reduction of cisplatin responsiveness. Therefore, novel therapeutic strategies for TGCTs are needed. System L amino acid transporters have been reported to be up‐regulated and to play an important role in tumorigenesis. However, expression and role of system L amino acid transporters in TGCTs remain elusive. Materials and methods Expression of system L amino acid transporters was analyzed in TGCT samples from The Cancer Genome Atlas (TCGA). Expression of LAT1, LAT2, and 4F2hc was examined in human embryonal carcinoma cell line NTERA2. Roles of system L amino acid transporters on NTERA2 cell survival, cell proliferation, pluripotency, and cisplatin sensitivity were evaluated. Results Based upon TCGA datasets, we found that two isoforms of system L (LAT1 and LAT2) and their chaperone protein 4F2hc are highly expressed in EC samples compared with other groups. Treatment with the system L inhibitor BCH significantly suppressed leucine uptake into the pluripotent EC cell line NTERA2. The malignant phenotypes including cell viability, cell proliferation, and clonal ability were decreased following BCH treatment. Nonetheless, system L inhibition did not alter expression of stemness genes in NTERA2 cells. After NTERA2 differentiation, expressions of LAT1 and LAT2 were decreased. Finally, co‐administration of BCH enhanced cisplatin sensitivity in both undifferentiated and differentiated cells. These effects were associated with the reduction in p70S6K phosphorylation. Conclusion Taken together, these results shed light on the roles of system L amino acid transporters in TGCTs. Therefore, system L amino acid transporters could provide novel therapeutic targets for treatment against TGCTs.

Contribution of the L-Type Amino Acid Transporter Family in the Diagnosis and Treatment of Prostate Cancer

“…4F2hc is required for the transport of LAT1 and LAT2 to the plasma membrane [ 9 ], where LAT1 and LAT2 are thought to determine the transport properties of heterodimers. At the same time, increased 4F2hc expression levels in many forms of cancer are associated with poorer prognosis in several studies [ 33 , 34 , 35 , 36 ] ( Figure 2 ).…”

Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways

“…It is obvious that LAT1 and 4F2hc cannot work alone without each other. Meanwhile, in many forms of cancer, increased 4F2hc expression levels have been linked to a worse prognosis in several studies [ 24 , 25 , 26 , 27 ]. The most critical structure involved in the interaction of the complex is the disulfide bond between the two proteins [ 8 , 23 ].…”