2016 Fiscal Year Final Research Report
ER-stress loading therapy in refractory multiple myeloma
| 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(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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| 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 |
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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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| Free Research Field |
腫瘍学
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