Selective Inhibition of L-type Amino Acid Transporter 1 Suppresses Cell Proliferation in Ovarian Clear Cell Carcinoma

by Selleckchem | Aug 20 2023

Background/aim: Ovarian clear cell carcinoma (OCCC) is a histological type of ovarian cancer that is refractory to chemotherapy and has poor prognosis, which necessitates the development of novel treatment therapies. In this study, we focused on L-type amino acid transporter 1 (LAT1), which is involved in cancer growth, and investigated the effect of its selective inhibition on cell proliferation in OCCC.

Materials and methods: The inhibitory effect of nanvuranlat (JPH203), a LAT1 selective inhibitor, on the cellular uptake of [3H] leucine was evaluated using the OCCC cell line JHOC9, which expresses the LAT1 protein. In addition, the kinetics of cell proliferation and changes in phosphorylation of the mTOR pathway were analyzed. The correlation between LAT1 expression and progression-free survival (PFS) was evaluated using clinical specimens of OCCC.

Results: Nanvuranlat inhibited [3H] leucine intracellular uptake and cell proliferation in a dose-dependent manner in JHOC9 cells. In addition, it suppressed the activity of the mTOR signaling pathway, which is thought to inhibit cancer cell proliferation. LAT1 expression was most frequent in OCCC among clinical specimens of epithelial ovarian cancer. A correlation between LAT1 expression and PFS was observed in OCCC.

Conclusion: LAT1 selective inhibition suppresses cell proliferation via the mTOR pathway by inhibiting leucine uptake in OCCC. This study illustrates the potential of using LAT1 selective inhibition as a treatment strategy for OCCC.

Comments:

The aim of the study was to investigate the effect of selective inhibition of L-type amino acid transporter 1 (LAT1) on cell proliferation in ovarian clear cell carcinoma (OCCC), a type of ovarian cancer that is resistant to chemotherapy and has a poor prognosis. The researchers used a selective LAT1 inhibitor called nanvuranlat (JPH203) and evaluated its inhibitory effect on the uptake of [3H] leucine, a marker for LAT1 activity, in the OCCC cell line JHOC9. They also analyzed the kinetics of cell proliferation and changes in the phosphorylation of the mTOR pathway, which is involved in cancer cell growth. Furthermore, the correlation between LAT1 expression and progression-free survival (PFS) was assessed using clinical specimens of OCCC.

The results of the study demonstrated that nanvuranlat inhibited the intracellular uptake of [3H] leucine and cell proliferation in a dose-dependent manner in the JHOC9 cells. It also suppressed the activity of the mTOR signaling pathway, which is known to promote cancer cell proliferation. LAT1 expression was found to be most frequent in OCCC among the clinical specimens of epithelial ovarian cancer examined. Additionally, a correlation between LAT1 expression and PFS was observed in OCCC, suggesting that LAT1 may play a role in disease progression.

Based on these findings, the study suggests that selective inhibition of LAT1 can suppress cell proliferation through the mTOR pathway by blocking leucine uptake in OCCC. This highlights the potential of targeting LAT1 as a treatment strategy for OCCC, which currently lacks effective therapeutic options. The study provides valuable insights into the role of LAT1 in OCCC and supports further investigation into LAT1 inhibitors as potential therapeutic agents for this aggressive form of ovarian cancer.