Molecular mechanism of therapy-induced senescence caused by replicative stress

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03598
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kyushu University
• Principal Investigator: Kitao Hiroyuki 九州大学, 薬学研究院, 教授 (30368617)
• Co-Investigator(Kenkyū-buntansha): 飯森 真人 九州大学, 薬学研究院, 准教授 (20546460) ; 釣本 敏樹 九州大学, 理学研究院, 教授 (30163885) ; 沖 英次 九州大学, 大学病院, 講師 (70380392) ; 佐伯 浩司 群馬大学, 大学院医学系研究科, 教授 (80325448) ; 三浦 大典 九州大学, 農学研究院, 特任准教授 (40532627)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 抗がん剤 / DNA複製ストレス / 治療誘導性細胞老化

Outline of Final Research Achievements

Therapy-induced senescence is now recognized as an important mechanism that elucidates irreversible cell cycle arrest induced by chemotherapeutic drugs. In this research project, we found that trifluridine, a cytotoxic component of chemotherapeutic drug FTD/TPI, efficiently induced cellular senescence in the cell culture condition and DNA replication stress induced by trifluridine was the trigger. In tumor cells, trifluridine, as a fluorinated thymidine analog, was incorporated into genomic DNA during DNA replication process. At that process, trifluridine decreased the efficiency of DNA replication. As a result, single-strand DNA was exposed in the nucleus, p53 was activated, and cellular senescence was induced. In the tumor cells with p53 deficiency, apoptosis was induced as a result of abnormal sister chromatid separation.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

FTD/TPIは進行大腸癌・胃癌に対する抗がん剤として世界で広く治療に用いられている。本研究成果は、FTD/TPIの抗腫瘍効果を担うFTDの作用メカニズムの理解に必須の知見である。さらに、悪性度を増したヒト腫瘍で多く見られ、抗がん剤耐性に繋がるとされるp53欠損を持つがん細胞であってもFTDが抗腫瘍効果を発揮するという結果は、このメカニズムに基づく抗がん剤治療がp53変異に関わらず有効であることを示唆しており、今後の抗がん剤開発を考える上でも意義は大きい。