A novel therapeutic method for multiple myeloma by comprehensive control of intracellular protein degradation mechanism
| Project/Area Number |
17K08771
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
平本 正樹 東京医科大学, 医学部, 准教授 (70297828)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 多発性骨髄腫 / オートファジー / プロテアソーム / アグリソーム / 小胞体ストレス / マクロライド系抗生剤 / アポトーシス / ボルテゾミブ / 腫瘍 |
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| Outline of Final Research Achievements |
We succeeded in identifying the target molecule Protein-X in the autophagy inhibitory activity of azithromycin by affinity purification using FG beads. In addition to autophagy inhibition by macrolide and proteasome inhibitor, a combination of SAHA having the HDAC6 inhibitory effect resulted in the maximum level of ER stress loading as well as the induction of the most potent cell-killing effect in myeloma cell lines. These results strongly suggest the existence of an intracellular network between autophagy, proteasome, and aggresome formation.
Our results indicate that systematically block the linkage between this network by using the existing drugs can achieve efficient myeloma cell death via ER stress loading, which we describe “ER-stress loading therapy”.
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| Academic Significance and Societal Importance of the Research Achievements |
細胞内の二大タンパク質分解機構であるユビキチン・プロテアソーム系とオートファジー・リソソーム系に加えてアグリソーム形成が、不良タンパク質処理に協同して機能しているとを明らかにした。また、この相互作用を既存薬を用いて計画的に阻害することで、小胞体ストレス負荷を介した強力なアポトーシス誘導を腫瘍細胞に惹起できることを明らかにした。
これより難治性骨髄腫に対する「小胞体ストレス療法」という、新規治療概念を提唱することができた。
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Report
(4 results)
Research Products
(36 results)
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[Journal Article] Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis.2018
Author(s)
Saito Y, Moriya S, Kazama H, Hirasawa K, Miyahara K, Kokuba H, Hino H, Kikuchi H, Takano N, Hiramoto M, Tsukahara K, Miyazawa K.
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Journal Title
Int J Oncol.
Volume: 52
Pages: 1165-1177
DOI
Related Report
Peer Reviewed / Open Access
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