Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines.
Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines.
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DOI：
10.3892/ijo.2016.3673
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发表时间：
2016-11
影响因子：
5.2
通讯作者：
Miyazawa K
中科院分区：
文献类型：
--
作者：
Miyahara K;Kazama H;Kokuba H;Komatsu S;Hirota A;Takemura J;Hirasawa K;Moriya S;Abe A;Hiramoto M;Ishikawa T;Miyazawa K
泛素-蛋白酶体和自噬-溶酶体途径是细胞蛋白质的两个主要自消化系统。泛素化错误折叠蛋白主要被蛋白酶体降解。然而，当泛素化蛋白积累超过蛋白酶体清除能力时，它们会沿着微管转运到微管组织中心（MTOC）形成聚集体，随后其中一些被自噬-溶酶体系统降解。我们之前报道过，阿奇霉素和克拉霉素等大环内酯类抗生素可阻断自噬流，并且蛋白酶体抑制剂硼替佐米（BZ）和大环内酯类药物联合治疗可增强乳腺癌细胞中内质网（ER）应激介导的细胞凋亡。由于泛素化蛋白在蛋白酶体失效后集中在攻击体上，因此我们将重点放在微管上，作为攻击体形成的运输途径的支架。用 BZ 处理转移性乳腺癌细胞系（例如 MDA-MB-231 细胞）会诱导聚集体，免疫细胞化学检测到聚集体为在核周病变中形成的独特的眼球状波形蛋白阳性包涵体，电子显微镜检测到聚集体为具有一些致密无定形沉积物的纤维结构球体。抑制微管聚合的长春瑞滨 (VNR) 比稳定微管的紫杉醇 (PTX) 更有效地抑制 BZ 诱导的聚集体形成。使用 BZ 和 VNR（而非 PTX）的联合治疗增强了细胞毒性作用和细胞凋亡诱导，并伴有明显的 ER 应激负荷，例如 GRP78 和 CHOP/GADD153 的上调。在含有 BZ 和 VNR 的细胞培养物中添加阿奇霉素来阻断自噬流，进一步增强了细胞毒性。这些数据表明，使用抑制药物（例如用于微管聚合的 VNR）抑制 BZ 诱导的聚集体形成是转移性乳腺癌治疗的一种新策略。
The ubiquitin-proteasome and autophagy-lysosome pathways are two major self-digestive systems for cellular proteins. Ubiquitinated misfolded proteins are degraded mostly by proteasome. However, when ubiquitinated proteins accumulate beyond the capacity of proteasome clearance, they are transported to the microtubule-organizing center (MTOC) along the microtubules to form aggresomes, and subsequently some of them are degraded by the autophagy-lysosome system. We previously reported that macrolide antibiotics such as azithromycin and clarithromycin block autophagy flux, and that concomitant treatment with the proteasome inhibitor bortezomib (BZ) and macrolide enhances endoplasmic reticulum (ER) stress-mediated apoptosis in breast cancer cells. As ubiquitinated proteins are concentrated at the aggresome upon proteasome failure, we focused on the microtubule as the scaffold of this transport pathway for aggresome formation. Treatment of metastatic breast cancer cell lines (e.g., MDA-MB-231 cells) with BZ resulted in induction of aggresomes, which immunocytochemistry detected as a distinctive eyeball-shaped vimentin-positive inclusion body that formed in a perinuclear lesion, and that electron microscopy detected as a sphere of fibrous structure with some dense amorphous deposit. Vinorelbine (VNR), which inhibits microtubule polymerization, more effectively suppressed BZ-induced aggresome formation than paclitaxel (PTX), which stabilizes microtubules. Combined treatment using BZ and VNR, but not PTX, enhanced the cytotoxic effect and apoptosis induction along with pronounced ER stress loading such as upregulation of GRP78 and CHOP/GADD153. The addition of azithromycin to block autophagy flux in the BZ plus VNR-containing cell culture further enhanced the cytotoxicity. These data suggest that suppression of BZ-induced aggresome formation using an inhibitory drug such as VNR for microtubule polymerization is a novel strategy for meta-static breast cancer therapy.
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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：
64.5
作者：
Brodsky JL
通讯作者：
Brodsky JL
影响因子：
5.2
作者：
Moriya S;Komatsu S;Yamasaki K;Kawai Y;Kokuba H;Hirota A;Che XF;Inazu M;Gotoh A;Hiramoto M;Miyazawa K
通讯作者：
Miyazawa K
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP