Re-sensitization of drug-resistant cancer cells by targeting hexosamine signaling pathways

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K06671
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kyoto Sangyo University
• Principal Investigator: Itano Naoki 京都産業大学, 生命科学部, 教授 (40257712)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: がん幹細胞 / 薬剤耐性 / ヒアルロン酸 / O-GlcNAc修飾 / ヘキソサミンシグナル

Outline of Final Research Achievements

Cancer stem cells (CSCs) are self-renewing cancer cells that have been implicated in cancer recurrence and resistance to therapy and are considered promising targets for cancer therapy. The hexosamine biosynthetic pathway (HBP) is emerging as a nutrient sensor that integrates nutrient availability with numerous intracellular signaling networks. In this study, we investigated the role of HBP and its downstream signaling in CSC regulation and found that HBP flux comprehensively regulates CSC-like features by driving hyaluronan and O-GlcNAcylation signaling pathways. Furthermore, we found that hyaluronan signaling triggers the Akt/GSK3β/β-catenin signaling pathway and promotes cell survival and drug-resistance.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果として、ヘキソサミン合成経路とその下流シグナルであるヒアルロン酸糖鎖シグナルやO-GlcNAc修飾シグナルが、薬剤耐性がん幹細胞の制御にはたらくことを明らかにした。この成果は、がん幹細胞性の制御機構解明にとって重要であり、学術的意義がある。またこの成果を通じて、ヘキソサミン合成経路の代謝酵素やO-GlcNAc修飾酵素を標的とした創薬への展開が期待でき、がんの薬剤耐性を制御する新たな治療戦略の可能性を拡げる。