| Project/Area Number |
26460478
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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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| Co-Investigator(Renkei-kenkyūsha) |
HANDA Hiroshi 東京医科大学, 医学部, 特任教授 (80107432)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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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 / 小胞体ストレス / マクロライド抗生剤 / アグリソーム / プロテアソーム阻害剤 / ボルテゾミブ / マクロライド化合物 / ヒストン脱アセチル化酵素６ |
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| Outline of Final Research Achievements |
Combined treatment with bortezomib (BZ）and a macrolide for the simultaneous blocking of proteasome and autophagy pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via ER stress overloading. As misfolded protein cargo is recruited by HDAC 6 to dynein motors for aggresome transport， serving to sequester misfolded proteins, we investigated the cellular effects of targeting proteolytic pathways and aggresome concomitantly in MM cells.
Pronounced apoptosis was induced by the combination of vorinostat (SAHA; potently inhibits HDAC 6) with CA M and BZ compared with each reagent or a 2-reagent combination. CAM/BZ treatment induced vimentin positive-aggresome formation, whereas it was inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including CHOP.
Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient ER stress-mediated apoptosis in MM cells.
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