Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells
Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells
复制标题
同时抑制泛素蛋白酶体系统和自噬可增强人胰腺癌细胞内质网应激加重剂诱导的细胞凋亡
DOI：
10.1080/15548627.2016.1191722
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Qin, Renyi
中科院分区：
文献类型：
--
作者：
Li, Xu;Zhu, Feng;Qin, Renyi
与正常组织相比，癌细胞在蛋白质合成和降解方面表现出深刻的变化。因此，调节内质网（ER）稳态的蛋白质越来越被认为是潜在的治疗靶点。泛素-蛋白酶体系统和自噬对细胞内的蛋白质平衡至关重要。然而，癌症中自噬、蛋白酶体和内质网应激途径之间的相互作用在很大程度上仍不清楚。本研究表明，从Withania somnifera中提取的具有生物活性的withaferin-A （WA）可以显著增加人胰腺癌（PC）细胞中的自噬体，但通过抑制snare介导的自噬体和溶酶体融合来阻止自噬物质的降解。WA特异性诱导蛋白酶体抑制，促进泛素化蛋白的积累，导致内质网应激介导的细胞凋亡。同时，WA诱导的早期自噬受损可能是响应内质网应激而激活的。重要的是，WA与一系列内质网应激加重剂联合使用可协同促进细胞凋亡。WA在小鼠中耐受性良好，并与内质网应激加重因子协同抑制异种PC移植瘤的生长。综上所述，这些发现表明，同时抑制2个关键的细胞内蛋白降解系统使PC细胞易受内质网应激的影响，这可能为这种疾病的新治疗组合提供了一条途径。
ABSTRACT In contrast to normal tissue, cancer cells display profound alterations in protein synthesis and degradation. Therefore, proteins that regulate endoplasmic reticulum (ER) homeostasis are being increasingly recognized as potential therapeutic targets. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. However, interactions between autophagy, the proteasome, and ER stress pathways in cancer remain largely undefined. This study demonstrated that withaferin-A (WA), the biologically active withanolide extracted from Withania somnifera, significantly increased autophagosomes, but blocked the degradation of autophagic cargo by inhibiting SNARE-mediated fusion of autophagosomes and lysosomes in human pancreatic cancer (PC) cells. WA specifically induced proteasome inhibition and promoted the accumulation of ubiquitinated proteins, which resulted in ER stress-mediated apoptosis. Meanwhile, the impaired autophagy at early stage induced by WA was likely activated in response to ER stress. Importantly, combining WA with a series of ER stress aggravators enhanced apoptosis synergistically. WA was well tolerated in mice, and displayed synergism with ER stress aggravators to inhibit tumor growth in PC xenografts. Taken together, these findings indicate that simultaneous suppression of 2 key intracellular protein degradation systems rendered PC cells vulnerable to ER stress, which may represent an avenue for new therapeutic combinations for this disease.