蛋白酶体抑制剂已通过积累有毒的错误折叠蛋白质而应用于抗癌治疗。然而，蛋白酶体的化学灭活会产生聚集体，这是一种波形蛋白笼封闭的亚细胞结构，在蛋白质毒物被自噬降解之前隔离 HDAC6-动力蛋白转运的错误折叠蛋白质。因此，聚集体可以减弱蛋白酶体抑制剂药物诱导的细胞毒性。为了解决这个问题，必须描述细胞如何聚集。通过检查六种细胞系中的聚集体，选择性地研究了 A549 细胞的较大细胞尺寸和中等聚集体形成活性。 A549 细胞持续暴露于蛋白酶体抑制剂 MG132 后，聚集体尺寸不断增大，并在处理的第 16 至 24 小时左右达到成熟尺寸。机制研究表明，在 MG132 处理的细胞中，NF-кB 易位至细胞核，并且 NF-кB 的化学激活或敲低可增强或阻止攻击体组装。进一步的分析表明，NF-кB 上调 HDAC6，并且 HDAC6 通过与波形蛋白 p72 相互作用维持波形蛋白笼，波形蛋白 p72 是促进聚集体形成的中间丝的关键修饰。值得注意的是，NF-кB 的化学灭活可协同 MG132 诱导的细胞死亡率。所有研究结果表明，NF-кB 通过上调 HDAC6 来控制聚集体组装，并且 NF-кB 抑制剂可能作为一种潜在的药物，在癌细胞治疗过程中增强蛋白酶体抑制剂药物诱导的细胞毒性。

Proteasome inhibitors have been applied to anticancer therapy by accumulating toxic misfolded proteins. However, chemical inactivation of proteasome generates aggresome, a Vimentin cage-enclosed subcellular structure quarantining HDAC6-Dynein-transported misfolded proteins before the protein toxicants are degraded by autophagy. Hence, aggresome may attenuate proteasome inhibitor drugs-induced cytotoxicity. To solve the problem, it is imperative to characterize how cells assemble aggresome. By examining aggresomes in six cell lines, A549 cells were selectively studied for their bigger cell size and moderate aggresome forming activity. Aggresome grew in size upon continuous exposure of A549 cells to proteasome inhibitor MG132, and reached a mature size around 16th to 24th hour of treatment. Mechanistic studies revealed that NF-кB translocated to nucleus in MG132 treated cells, and chemical activation or knockdown of NF-кB enhanced or prohibited aggresome assembly. Further analyses showed that NF-кB upregulated HDAC6, and HDAC6 maintained Vimentin cage by interacting with Vimentin p72, a key modification of the intermediate filament contributing to aggresome formation. Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.