LAT1 inhibitor JPH203 sensitizes cancer cells to radiation by enhancing radiation-induced cellular senescence

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22830
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Yamagata University
• Principal Investigator: BO Tomoki 山形大学, 医学部, 助教 (90878141)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: がん / 放射線 / 中性アミノ酸代謝 / LAT1

Outline of Final Research Achievements

We previously demonstrated that radiation activated energy metabolism and increased neutral amino acid content in cancer cells. We speculated that neutral amino acid metabolism can be a target for cancer radiation therapy. In this study, we examined the effect of neutral amino acid transporter, L-type amino acid transporter 1 (LAT1) inhibition on radiosensitivity after irradiation.
We showed that LAT1 inhibitor JPH203 inhibited the radiation-induced increase in neutral amino acid uptake. We also demonstrated that JPH203, at minimally toxic concentrations, significantly sensitized cancer cells to radiation. In addition, JPH203 significantly downregulated mTOR activity and enhanced cellular senescence post-irradiation. These results indicate that LAT1 inhibition by JPH203 sensitizes cancer cells to radiation by enhancing cellular senescence via mTOR downregulation. Thus, neutral amino acid metabolism may be a potent target of cancer radiation therapy.

Free Research Field

放射線生物学

Academic Significance and Societal Importance of the Research Achievements

本研究はLAT1を介して取込まれる中性アミノ酸が放射線照射を受けたがん細胞の生存に重要であることを明らかにしたことから、放射線生物学の知見を一層深化させた。
また、本研究はLAT1を標的としたがん治療薬JPH203が放射線増感を引き起こすことを明らかにした初の研究報告である。JPH203が放射線療法との併用されることで今後臨床応用される可能性を提示し、社会的意義も高い研究内容である。