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Article

L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells

by 1,†, 2,3,†, 1, 2, 4, 3,5,6,7,8,9,* and 2,10,*
1
Department of Pulmonary Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan
2
Department of Biomedical Sciences, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan
3
Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, No. 135 Nanhsiao Str., Changhua City 50006, Taiwan
4
Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan
5
School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan
6
School of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Sanmin Dist., Kaohsiung City 80708, Taiwan
7
Institute of Genomics and Bioinformatics, National Chung Hsing University, No. 145 Xingda Rd., South Dist., Taichung City 40227, Taiwan
8
College of Medicine, National Chung Hsing University, No. 145 Xingda Rd., South Dist., Taichung City 40227, Taiwan
9
Ph.D. Program in Translational Medicine, National Chung Hsing University, No. 145 Xingda Rd., South Dist., Taichung City 40227, Taiwan
10
Department of Medical Research, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Carlo Genova
Int. J. Mol. Sci. 2021, 22(20), 10955; https://doi.org/10.3390/ijms222010955
Received: 24 August 2021 / Revised: 29 September 2021 / Accepted: 8 October 2021 / Published: 11 October 2021
The l-type amino acid transporter 1 (LAT1) is a membranous transporter that transports neutral amino acids for cells and is dysregulated in various types of cancer. Here, we first observed increased LAT1 expression in pemetrexed-resistant non-small cell lung cancer (NSCLC) cells with high cancer stem cell (CSC) activity, and its mRNA expression level was associated with shorter overall survival in the lung adenocarcinoma dataset of the Cancer Genome Atlas database. The inhibition of LAT1 by a small molecule inhibitor, JPH203, or by RNA interference led to a significant reduction in tumorsphere formation and the downregulation of several cancer stemness genes in NSCLC cells through decreased AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) activation. The treatment of the cell-permeable leucine derivative promoted AKT/mTOR phosphorylation and reversed the inhibitory effect of JPH203 in the reduction of CSC activity in pemetrexed-resistant lung cancer cells. Furthermore, we observed that LAT1 silencing caused the downregulation of programmed cell death 1 ligand 1 (PD-L1) on lung cancer cells. The PD-L1+/LAT1+ subpopulation of NSCLC cells displayed great CSC activity with increased expression of several cancer stemness genes. These data suggest that LAT1 inhibitors can serve as anti-CSC agents and could be used in combination with immune checkpoint inhibitors in lung cancer therapy. View Full-Text
Keywords: LAT1; PD-L1; cancer stem cells; non-small cell lung cancer LAT1; PD-L1; cancer stem cells; non-small cell lung cancer
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Figure 1

MDPI and ACS Style

Liu, Y.-H.; Li, Y.-L.; Shen, H.-T.; Chien, P.-J.; Sheu, G.-T.; Wang, B.-Y.; Chang, W.-W. L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells. Int. J. Mol. Sci. 2021, 22, 10955. https://doi.org/10.3390/ijms222010955

AMA Style

Liu Y-H, Li Y-L, Shen H-T, Chien P-J, Sheu G-T, Wang B-Y, Chang W-W. L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells. International Journal of Molecular Sciences. 2021; 22(20):10955. https://doi.org/10.3390/ijms222010955

Chicago/Turabian Style

Liu, Yi-Heng, Yu-Ling Li, Huan-Ting Shen, Peng-Ju Chien, Gwo-Tarng Sheu, Bing-Yen Wang, and Wen-Wei Chang. 2021. "L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells" International Journal of Molecular Sciences 22, no. 20: 10955. https://doi.org/10.3390/ijms222010955

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