Glycogen synthase kinase 3beta as a potential therapeutic target in synovial sarcoma and fibrosarcoma

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K10850
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kanazawa University
• Principal Investigator: YAMAMOTO NORIO 金沢大学, 医薬保健学総合研究科, 特任教授 (90332668)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: GSK3β / 軟部肉腫 / 分子標的治療

Outline of Final Research Achievements

We investigated the expression, activity and putative pathological role of GSK3β in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3β was higher in synovial sarcoma and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3β activity by pharmacological agents or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, CDK4 and MMP2. Intraperitoneal injection of the GSK3β inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice.

Free Research Field

骨軟部腫瘍

Academic Significance and Societal Importance of the Research Achievements

本邦では2012年より，軟部肉腫に対してパゾパニブの使用が承認されが，残念ながら既存の抗癌剤を上回る効果は得られていない．GSK3βは，グリコーゲン合成酵素をリン酸化して不活性化させる酵素である．本研究では，軟部肉腫の主要病型である滑膜肉腫と線維肉腫に対するGSK3β阻害剤の治療効果と作用機序を検討し，腫瘍の生存，増殖，浸潤にGSK3βが大きく関連していることを明らかとした．GSK3β活性阻害作用を有する薬剤は，既に実臨床で使用されており，新たな軟部肉腫の分子標的治療薬になる可能性がある．本研究で得られた成果は，新たな軟部肉腫治療薬の開発に大きく寄与する，社会的意義の高い研究成果だといえる．