MUC1c regulates cell survival in pancreatic cancer by preventing lysosomal permeabilization.
MUC1c regulates cell survival in pancreatic cancer by preventing lysosomal permeabilization.
复制标题
DOI：
10.1371/journal.pone.0043020
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Saluja AK
中科院分区：
文献类型：
--
作者：
Banerjee S;Mujumdar N;Dudeja V;Mackenzie T;Krosch TK;Sangwan V;Vickers SM;Saluja AK
MUC 1是一种I型跨膜糖蛋白，在包括胰腺癌在内的多种癌细胞中异常过表达。MUC 1的胞质末端（MUC 1-c）广泛参与许多信号通路。据报道MUC 1-c在许多癌细胞中抑制凋亡，但抑制机制尚不清楚。在胰腺癌细胞系MIAPaCa-2中，通过使用qRTPCR在RNA水平上和通过蛋白质印迹在蛋白质水平上研究MUC 1-c的表达。MUC 1-c表达被siRNA或特异性肽抑制剂GO-201抑制。研究了MUC 1-c抑制对活力和增殖以及溶酶体透化的影响。通过MUC 1-c和HSP 70的免疫共沉淀检测MUC 1-c与HSP 70的结合。MUC 1-c在细胞器中的定位通过免疫荧光和在亚细胞分级分离后通过MUC 1-c抗体的免疫印迹来监测。通过抑制剂（GO-201）或siRNA抑制MUC 1-c导致胰腺癌细胞的活力降低和增殖减少。此外，MUC 1-c的肽抑制剂GO-201可有效降低胰腺癌小鼠模型的肿瘤负荷。还发现MUC 1-c与胞质溶胶中的HSP 70相关，尽管在溶酶体中也发现了大量的MUC 1。MUC 1表达或活性的抑制显示胞质溶胶中组织蛋白酶B活性增强，表明溶酶体透化。因此，本研究表明MUC 1-c与胰腺癌细胞胞浆中的HSP 70相互作用，并定位于这些细胞中的溶酶体。此外，我们的结果表明，MUC 1-c通过稳定溶酶体和防止细胞溶质中组织蛋白酶B的释放来保护胰腺癌细胞免于细胞死亡。
MUC1 is a type I transmembrane glycoprotein aberrantly overexpressed in various cancer cells including pancreatic cancer. The cytosolic end of MUC1 (MUC1-c) is extensively involved in a number of signaling pathways. MUC1-c is reported to inhibit apoptosis in a number of cancer cells, but the mechanism of inhibition is unclear. Expression of MUC1-c was studied in the pancreatic cancer cell line MIAPaCa-2 at the RNA level by using qRTPCR and at the protein level by Western blotting. MUC1-c expression was inhibited either by siRNA or by a specific peptide inhibitor, GO-201. Effect of MUC1-c inhibition on viability and proliferation and lysosomal permeabilization were studied. Association of MUC1-c with HSP70 was detected by co-immunoprecipitation of MUC1-c and HSP70. Localization of MUC1-c in cellular organelles was monitored by immunofluorescence and with immuno- blotting by MUC1-c antibody after subcellular fractionation. Inhibition of MUC1-c by an inhibitor (GO-201) or siRNA resulted in reduced viability and reduced proliferation of pancreatic cancer cells. Furthermore, GO-201, the peptide inhibitor of MUC1-c, was effective in reducing tumor burden in pancreatic cancer mouse model. MUC1-c was also found to be associated with HSP70 in the cytosol, although a significant amount of MUC1 was also seen to be present in the lysosomes. Inhibition of MUC1 expression or activity showed an enhanced Cathepsin B activity in the cytosol, indicating lysosomal permeabilization. Therefore this study indicates that MUC1-c interacted with HSP70 in the cytosol of pancreatic cancer cells and localized to the lysosomes in these cells. Further, our results showed that MUC1-c protects pancreatic cancer cells from cell death by stabilizing lysosomes and preventing release of Cathepsin B in the cytosol.
登录
查看更多内容
影响因子：
3.2
作者：
Croce, MV;Isla-Larrain, MT;Segal-Eiras, A
通讯作者：
Segal-Eiras, A
MUC1癌蛋白通过抑制caspase-8的募集来阻断死亡受体介导的凋亡。
影响因子：
11.2
作者：
Agata, Naoki;Ahmad, Rehan;Kawano, Takeshi;Raina, Deepak;Kharbanda, Surender;Kufe, Donald
通讯作者：
Kufe, Donald
影响因子：
11.2
作者：
Daugaard, Mads;Kirkegaard-Sorensen, Thomas;Jaattela, Marja
通讯作者：
Jaattela, Marja
影响因子：
78.5
作者：
Kufe, Donald W.
通讯作者：
Kufe, Donald W.
影响因子：
4.8
作者：
Burdick, MD;Harris, A;Hollingsworth, MA
通讯作者：
Hollingsworth, MA