Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress‑mediated cell death in multiple myeloma cells.
Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress‑mediated cell death in multiple myeloma cells.
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DOI：
10.3892/ijo.2014.2773
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发表时间：
2015-02
影响因子：
5.2
通讯作者：
Miyazawa K
中科院分区：
文献类型：
--
作者：
Moriya S;Komatsu S;Yamasaki K;Kawai Y;Kokuba H;Hirota A;Che XF;Inazu M;Gotoh A;Hiramoto M;Miyazawa K
包括克拉霉素（CAM）在内的大环内酯类抗生素对自噬通量的抑制作用已有报道。尽管大环内酯类抗生素没有细胞毒性，但其与蛋白酶体抑制剂硼替佐米（BZ）组合用于同时阻断泛素（Ub）-蛋白酶体和自噬-溶酶体途径，导致通过内质网（ER）的应激过载增强多发性骨髓瘤（MM）细胞凋亡诱导。由于错误折叠的蛋白质货物被组蛋白脱乙酰酶6（HDAC 6）募集到动力蛋白马达用于攻击性蛋白组转运，从而用于螯合错误折叠的蛋白质，我们进一步研究了MM细胞中靶向蛋白水解途径和攻击性蛋白组形成的细胞效应。与每种试剂或2种试剂组合相比，伏立诺他[辛二酰苯胺异羟肟酸（SAHA）;强效抑制HDAC 6]与CAM和BZ的组合诱导了明显的细胞凋亡。CAM/BZ处理诱导波形蛋白阳性侵袭体形成沿着自溶体在核周区域的积累，而SAHA存在时它们被抑制。SAHA/CAM/BZ组合处理最大程度地上调与ER应激相关的基因，包括C/EBP同源蛋白（CHOP）。与MM细胞系类似，野生型鼠胚胎成纤维细胞（MEF）细胞系显示SAHA/CAM/BZ处理后CHOP上调的细胞毒性增强;然而，CHOP缺陷型MEF细胞系几乎完全消除了这种明显的细胞毒性。用siRNA敲低HDAC 6表现出进一步增强的CAM/BZ诱导的细胞毒性和CHOP诱导沿着攻击基因组形成的消除。提示靶向攻击体、蛋白酶体和自噬的整合网络可诱导MM细胞中有效的ER应激介导的凋亡。
The inhibitory effects of macrolide antibiotics including clarithromycin (CAM) on autophagy flux have been reported. Although a macrolide antibiotic exhibits no cytotoxicity, its combination with bortezomib (BZ), a proteasome inhibitor, for the simultaneous blocking of the ubiquitin (Ub)-proteasome and autophagy-lysosome pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via stress overloading of the endoplasmic reticulum (ER). As misfolded protein cargo is recruited by histone deacetylase 6 (HDAC6) to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of vorinostat [suberoylanilide hydroxamic acid (SAHA); potently inhibits HDAC6] with CAM and BZ compared with each reagent or a 2-reagent combination. CAM/BZ treatment induced vimentin positive-aggresome formation along with the accumulation of autolysosomes in the perinuclear region, whereas they were inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including C/EBP homologous protein (CHOP). Similarly to MM cell lines, enhanced cytotoxicity with CHOP upregulation following SAHA/CAM/BZ treatment was shown by a wild-type murine embryonic fibroblast (MEF) cell line; however, a CHOP-deficient MEF cell line almost completely canceled this pronounced cytotoxicity. Knockdown of HDAC6 with siRNA exhibited further enhanced CAM/BZ-induced cytotoxicity and CHOP induction along with the cancellation of aggresome formation. 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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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
20.3
作者：
Nawrocki, Steffan T.;Carew, Jennifer S.;McConkey, David J.
通讯作者：
McConkey, David J.
影响因子：
5.2
作者：
Komatsu S;Miyazawa K;Moriya S;Takase A;Naito M;Inazu M;Kohno N;Itoh M;Tomoda A
通讯作者：
Tomoda A