2021 Fiscal Year Final Research Report
Revealing of phosphorylation signaling in the downstream of LAT1 in cancer cells
| Project/Area Number |
19K16743
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 50010:Tumor biology-related
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | アミノ酸 / トランスポーター / プロテオミクス / リン酸化プロテオミクス / シグナル伝達 / アミノ酸トランスポーター |
|---|
| Outline of Final Research Achievements |
L-type amino acid transporter, LAT1, is highly expressed in cancers, and regulates phosphorylation signals which is stimulated by amino acids. We comprehensively elucidated LAT1-dependent phosphorylation dynamics in four biliary tract cancer cell lines sensitive to LAT1-specific inhibitor, JPH203. By using proteomic techniques, we analyzed changes in phosphorylation and protein expression induced by the LAT1 inhibitor. Thousands of differentially phosphorylated sites and differentially expressed proteins were identified, which suggests the broad influence of LAT1 on cancer cells. Molecular network analysis indicated influences of LAT1 inhibition on important pathways and regulators. Notably, inactivation of CDKs were found in all four cell lines. We found combination of CDK inhibitors and LAT1 inhibitor significantly reduced cancer cell proliferation compared with single inhibitor alone, which suggests clinical potentials of the combination in cancer therapies.
|
| Free Research Field |
プロテオーム解析
|
| Academic Significance and Societal Importance of the Research Achievements |
LAT1はがん細胞特異的に発現し，シグナル分子として働くアミノ酸の取り込みを介して細胞内環境を制御すると考えられている．しかし，mTORC1などよく知られた例以外はまだ不明な点が多かった．本研究により，LAT1阻害に伴う大規模なリン酸化動態変動が解明されたことは，今後のLAT1研究の基盤情報を提供するとともに，LAT1阻害による抗腫瘍作用を理解するために有用である．また，本研究ではがん細胞増殖抑制に関係する細胞周期停止におけるLAT1のかかわりを検証するのみならず，細胞周期関連リン酸化酵素阻害薬とLAT1阻害薬との併用で有用な抗腫瘍効果を明らかにした．これは今後の臨床応用可能性を示している．
|
