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

• Published in: International journal of molecular sciences 2021-10, Vol.22 (20), p.10955
• Main Authors: Liu, Yi-Heng, Li, Yu-Ling, Shen, Huan-Ting, Chien, Peng-Ju, Sheu, Gwo-Tarng, Wang, Bing-Yen, Chang, Wen-Wei
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; AKT protein; Amino acids; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Benzoxazoles - pharmacology; Breast cancer; cancer stem cells; Cancer therapies; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm - drug effects; Gene expression; Genes; Genomes; Humans; Immune checkpoint inhibitors; Kinases; Large Neutral Amino Acid-Transporter 1 - chemistry; Large Neutral Amino Acid-Transporter 1 - genetics; Large Neutral Amino Acid-Transporter 1 - metabolism; LAT1; Ligands; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical prognosis; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; non-small cell lung cancer; Non-small cell lung carcinoma; PD-L1; PD-L1 protein; Pemetrexed - pharmacology; Phosphorylation; Phosphorylation - drug effects; Protein expression; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; RNA Interference; RNA, Small Interfering - metabolism; RNA-mediated interference; Stem cells; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tyrosine - analogs & derivatives; Tyrosine - pharmacology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222010955

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.