GSK-3β signaling determines autophagy activation in the breast tumor cell line MCF7 and inclusion formation in the non-tumor cell line MCF10A in response to proteasome inhibition.
GSK-3β signaling determines autophagy activation in the breast tumor cell line MCF7 and inclusion formation in the non-tumor cell line MCF10A in response to proteasome inhibition.
复制标题
DOI：
10.1038/cddis.2013.95
复制
发表时间：
2013-04-04
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
泛素-蛋白酶体系统和自噬-溶酶体途径是真核细胞内蛋白质降解的两种主要机制。蛋白酶体抑制剂用于治疗某些类型的癌症，而自噬似乎在肿瘤细胞存活和死亡中具有双重作用。然而，这两种途径之间的关系尚未在肿瘤细胞中得到广泛研究。我们研究了人乳腺上皮非肿瘤细胞系MCF 10A和人乳腺上皮肿瘤细胞系MCF 7中的蛋白水解系统。在基础条件下，肿瘤细胞表现出较低的蛋白酶体功能，但较高的自噬活性相比，MCF 10A细胞。重要的是，蛋白酶体抑制（PI）导致两种细胞类型中的不同反应。肿瘤细胞显示出剂量依赖性糖原合成酶激酶-3（GSK-3）β抑制、转录因子CHOP表达的大幅增加和caspase-8的活性加工。相比之下，MCF 10A细胞完全激活GSK-3β，CHOP和加工的caspase-8的表达较低。这些分子差异反映在肿瘤细胞中剂量依赖性的自噬激活和细胞死亡中，而非肿瘤细胞则表现出包涵体的形成和细胞死亡率的降低。重要的是，当GSK-3β和蛋白酶体同时被抑制时，MCF 7细胞的行为可以在MCF 10A细胞中再现。在这种情况下，MCF 10A细胞强烈激活自噬，表现出最少的包涵体，CHOP表达增加和细胞死亡率增加。这些发现支持GSK-3β信号传导分别作为调节人类肿瘤或非肿瘤乳腺细胞中自噬激活或包涵体形成的关键机制，这可能为乳腺癌控制提供新的线索。
The ubiquitin–proteasome system and the autophagy–lysosome pathway are the two main mechanisms for eukaryotic intracellular protein degradation. Proteasome inhibitors are used for the treatment of some types of cancer, whereas autophagy seems to have a dual role in tumor cell survival and death. However, the relationship between both pathways has not been extensively studied in tumor cells. We have investigated both proteolytic systems in the human epithelial breast non-tumor cell line MCF10A and in the human epithelial breast tumor cell line MCF7. In basal condition, tumor cells showed a lower proteasome function but a higher autophagy activity when compared with MCF10A cells. Importantly, proteasome inhibition (PI) leads to different responses in both cell types. Tumor cells showed a dose-dependent glycogen synthase kinase-3 (GSK-3)β inhibition, a huge increase in the expression of the transcription factor CHOP and an active processing of caspase-8. By contrast, MCF10A cells fully activated GSK-3β and showed a lower expression of both CHOP and processed caspase-8. These molecular differences were reflected in a dose-dependent autophagy activation and cell death in tumor cells, while non-tumor cells exhibited the formation of inclusion bodies and a decrease in the cell death rate. Importantly, the behavior of the MCF7 cells can be reproduced in MCF10A cells when GSK-3β and the proteasome were simultaneously inhibited. Under this situation, MCF10A cells strongly activated autophagy, showing minimal inclusion bodies, increased CHOP expression and cell death rate. These findings support GSK-3β signaling as a key mechanism in regulating autophagy activation or inclusion formation in human tumor or non-tumor breast cells, respectively, which may shed new light on breast cancer control.
登录
查看更多内容
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
11.2
作者：
Fellerhoff, Barbara;Gu, Songhai;Wank, Rudolf
通讯作者：
Wank, Rudolf
影响因子：
3.3
作者：
Cook KL;Shajahan AN;Clarke R
通讯作者：
Clarke R
影响因子：
4
作者：
Haenssen, Keneshia K.;Caldwell, Sarah A.;Reginato, Mauricio J.
通讯作者：
Reginato, Mauricio J.
影响因子：
21.3
作者：
Lee, Jong-Soo;Li, Qinglin;Lee, June-Yong;Lee, Sun-Hwa;Jeong, Joseph H.;Lee, Hye-Ra;Chang, Heesoon;Zhou, Fu-Chun;Gao, Shou-Jiang;Liang, Chengyu;Jung, Jae U.
通讯作者：
Jung, Jae U.