Serine synthesis pathway activates de novo fatty acid synthesis to drive chemoresistance in malignant breast cancer.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Keio University
• Principal Investigator: Takehiro Yamamoto 慶應義塾大学, 医学部(信濃町), 講師 (50383774)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 乳がん / 治療抵抗性 / アルギニンメチル化 / 解糖系 / 脂肪酸代謝

Outline of Final Research Achievements

Although a number of anti-cancer drugs have been tried to target the vigorous proliferative capacity such as nucleic acid synthesis, rapid cell division, and accumulation of anti-oxidants. Unfortunately, the acquisition of resistance due to continuous chemotherapy is a major barrier in modern cancer treatment. In this study, we have elucidated a novel mechanism of resistance acquisition, namely, a metabolic pathway switch (remodeling) from the glycolytic pathway to the serine biosynthetic pathway mediated by arginine methylation of three metabolic enzymes (PFKFB3, PKM2, and PHGDH). We found that PHGDH, the rate-limiting enzyme of the serine synthesis pathway, undergoes methylation at R20 and R54 and enhances the ability to synthesize new fatty acids derived from the serine biosynthetic pathway.

Free Research Field

代謝生化学、病態医化学

Academic Significance and Societal Importance of the Research Achievements

本研究により、代謝酵素の高メチル化とその核局在は化学治療の奏功の指標となるばかりでなく、化学治療抵抗性乳がん細胞の脂肪酸代謝特性や翻訳後修飾に介入することで耐性を喪失させうる可能性を示唆しており、現時点で有望なマーカー分子が知られていない、トリプルネガティブ型の乳がんの代謝特性を明らかにした点で、本研究成果の社会的意義は大きいと考える。