2019 Fiscal Year Final Research Report

Elucidation of pathogenesis and development of therapeutic strategy of adult T-cell leukemia with a focus on nuclear transport protein importin

Research Project

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Project/Area Number	17K07175
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Tumor biology
Research Institution	University of the Ryukyus
Principal Investigator	Ishikawa Chie 琉球大学, 亜熱帯島嶼科学超域研究推進機構, 助教 (90542358)
Project Period (FY)	2017-04-01 – 2020-03-31
Keywords	成人T細胞白血病 / HTLV-1 / インポーチン / インポータゾル / イベルメクチン / NF-κB / AP-1 / 原発性体腔液性リンパ腫
Outline of Final Research Achievements	There is no cure for ATL associated with HTLV-1, and novel targeted strategies are needed. NF-κB/AP-1 are crucial for ATL, and both are transported to nucleus by an importin (IPO)α/β complex to activate target genes. We aimed to elucidate the function of IPO in ATL. IPOβ1 was upregulated in HTLV-1-infected T-cell lines, and viral infection can induce IPOβ1 expression in PBMCs. Further, IPOβ1 knockdown or IPOβ1 inhibitor importazole and IPOα/β1 inhibitor ivermectin reduced HTLV-1-infected T-cell proliferation. Inhibitors suppressed NF-κB/AP-1 nuclear transport and DNA binding, resulting in induction of G1 cell cycle arrest and caspase-3/8/9-dependent apoptosis. Moreover, the expression of NF-κB/AP-1-target proteins involved in cell cycle and apoptosis was reduced. In vivo, ivermectin decreased ATL tumor burden. IPOβ1 mediated NF-κB/AP-1 translocation into ATL cell nuclei, thereby regulating cell growth and survival, which provides new insights for targeted ATL therapies.
Free Research Field	ウイルス発がん
Academic Significance and Societal Importance of the Research Achievements	ATLは完治困難であり、その発症・進展にNF-κB/AP-1の活性化は重要であるが、両転写因子を直接の標的とした治療法の臨床応用には成功していない。本研究では、転写因子の輸送機序に着目し、核内輸送蛋白質IPOβ1の発現が、ウイルス感染で誘導され、NF-κB/AP-1の核内移行にIPOβ1が重要な役割を果たしていることを証明した。さらに、IPOβ1の阻害剤は感染T細胞株でのNF-κB/AP-1の標的蛋白質の発現を抑制し、細胞周期停止やアポトーシスを誘導した。マウスでの抗腫瘍効果の検証は、臨床応用への期待が高まる。本研究成果は、難治性の白血病の新規治療戦略を示しており、学術的・社会的意義は大きい。