Kim, S.-Y., Ong, Q., Liao, Y., Ding, Z., Tan, A. Q. L., Lim, L. T. R., Tan, H. M., Lim, S. L., Lee, Q. Y., & Han, W. (2023). Genetic Ablation of LAT1 Inhibits Growth of Liver Cancer Cells and Downregulates mTORC1 Signaling. International Journal of Molecular Sciences, 24(11), 9171. https://doi.org/10.3390/ijms24119171
Abstract:
Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 to knockout (KO) LAT1 in the epithelial HCC cell line, Huh7. Knockout of LAT1 diminished its branched chain amino acid (BCAA) transport activity and significantly reduced cell proliferation in Huh7. Consistent with in vitro studies, LAT1 ablation led to suppression of tumor growth in a xenograft model. To elucidate the mechanism underlying the observed inhibition of cell proliferation upon LAT1 KO, we performed RNA-sequencing analysis and investigated the changes in the mTORC1 signaling pathway. LAT1 ablation resulted in a notable reduction in phosphorylation of p70S6K, a downstream target of mTORC1, as well as its substrate S6RP. This reduced cell proliferation and mTORC1 activity were rescued when LAT1 was overexpressed. These findings imply an essential role of LAT1 for maintenance of tumor cell growth and additional therapeutic angles against liver cancer.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research is supported by core funding from: A*STAR BMRC
Grant Reference no. : SC15-R0069
This research / project is supported by the A*STAR - Strategic Research Program (Brain-Body Initiative)
Grant Reference no. : 21718
This research / project is supported by the National Research Foundation - Competitive Research Program
Grant Reference no. : NRF-CRP23-2019-0004
This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant (OF-YIRG)
Grant Reference no. : OFYIRG18May-0043