Elucidation of glutamine metabolism in tumor endothelial cells to develop novel anti-cancer drugs

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K19220
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Hokkaido University
• Principal Investigator: ANNAN DORCAS 北海道大学, 歯学研究院, 学術研究員 (30837240)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Tumor endothelial cell / Glutaminolysis / Glutamate / Glutathione / Tumor amgiogenesis / Oxidative stress / Sulfasalazine / Slc7a11/System -xc

Outline of Final Research Achievements

Tumor endothelial cells are the main focus of tumor angiogenesis studies. Compared to normal endothelial cells (NECs), TECs have a unique biology, which offers an explorable hub for new drug targets without the adverse side effects observed with common antiangiogenic drugs. The study examined the roles of glutamine metabolism and mitochondria in TECs. TECs had fewer mitochondria than NECs and produced more ATP from glycolysis than oxidative phosphorylation. Spare respiratory capacity was lower in TECs than in NECs. Glutamine utilization by TECs produced larger quantities of glutamate than other glutaminolysis metabolites. Consistently inhibition of the cystine/glutamate antiporter Slc7a11 with sulfasalazine (SSZ) decreased TEC proliferation more significantly than NECs after 72h although glutathione levels were rapidly decreased in all cells upon exposure. In the mouse tumor models, SSZ treatment decreased both tumor angiogenesis and tumor growth.

Free Research Field

細胞生物学，癌生物学

Academic Significance and Societal Importance of the Research Achievements

社会経済と人類の健康に癌が及ぼす悪い影響を取り除くためにも，癌の新しい治療戦略構築に関する研究の発展が望まれる．近年，癌細胞の代謝経路の標的化は創薬上重要な戦略と認識されている．本研究により，癌細胞のみならず腫瘍血管内皮細胞の代謝の特性も治療標的として有望であることが明らかになった．また，既存の血管新生阻害剤と異なり，より腫瘍血管に特異的な治療薬のための標的をこの研究にて提案することができた．このことにより，創薬研究分野に新たな知見を提供し，同時に新しい癌治療の展望をもたらした．