Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells.
Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells.
复制标题
蛋白酶体抑制剂将自噬作为人类前列腺癌细胞中的细胞保护反应。
DOI：
10.1038/onc.2009.343
复制
发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
McConkey, D J
中科院分区：
文献类型：
--
作者：
Zhu, K;Dunner, K Jr;McConkey, D J
泛素-蛋白酶体和溶酶体-自噬途径是两个主要的细胞内蛋白质降解系统，它们协同工作以维持体内平衡。蛋白酶体抑制剂(PI)在血液肿瘤中具有临床活性，自噬抑制剂也被评估为潜在的抗肿瘤治疗方法。在目前的研究中，我们发现，在一些人前列腺癌细胞和永生化的小鼠胚胎成纤维细胞(MEF)中，化学蛋白酶体抑制剂和siRNA介导的蛋白酶体亚基的敲除促进了自噬小体的形成，刺激了自噬通量，并上调了自噬特异性基因(ATG5和ATG7)的表达。ATG5和ATG7的上调只发生在PI诱导的真核细胞翻译起始因子2α(eIF2α)的磷酸化的细胞中，而eIF2 DNA是未折叠蛋白反应的重要组成部分。此外，PI没有诱导表达磷酸化缺陷的eIF2α突变形式的MEF的自噬或上调ATG5。联合抑制自噬和蛋白酶体诱导细胞内蛋白聚集物的积累，使人联想到神经元包涵体，并导致更多的癌细胞死亡，而不是单独阻止任何一条降解途径。总体而言，我们的数据表明，蛋白酶体抑制通过磷酸化eIF2α依赖的机制激活自噬，以消除蛋白质聚集并缓解蛋白毒性应激。
The ubiquitin-proteasome and lysosome-autophagy pathways are the two major intracellular protein degradation systems that work cooperatively to maintain homeostasis. Proteasome inhibitors (PIs) have clinical activity in hematological tumors, and inhibitors of autophagy are also being evaluated as potential antitumor therapies. In the current study we found that chemical proteasome inhibitors and siRNA-mediated knockdown of the proteasome's enzymatic subunits promoted autophagosome formation, stimulated autophagic flux, and upregulated expression of the autophagy specific genes (ATGs) (ATG5 and ATG7) in some human prostate cancer cells and immortalized mouse embryonic fibroblasts (MEFs). Upregulation of ATG5 and ATG7 only occurred in cells displaying PIs-induced phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF2α), an important component of the unfolded protein responses. Furthermore, PIs did not induce autophagy or upregulate ATG5 in MEFs expressing a phosphorylation-deficient mutant form of eIF2α. Combined inhibition of autophagy and the proteasome induced an accumulation of intracellular protein aggregates reminiscent of neuronal inclusion bodies and caused more cancer cell death than blocking either degradation pathway alone. Overall, our data demonstrate that proteasome inhibition activates autophagy via a phospho-eIF2α-dependent mechanism to eliminate protein aggregates and alleviate proteotoxic stress.