Ubiquitin-proteasome system stress sensitizes ovarian cancer to proteasome inhibitor-induced apoptosis
Ubiquitin-proteasome system stress sensitizes ovarian cancer to proteasome inhibitor-induced apoptosis
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DOI：
10.1158/0008-5472.can-05-2321
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Roden, RBS
中科院分区：
文献类型：
--
作者：
Bazzaro, M;Lee, MK;Roden, RBS
泛素-蛋白酶体系统（UPS）介导靶蛋白降解。值得注意的是，UPS通过控制蛋白质半衰期来确定控制细胞凋亡和增殖的关键检查点蛋白的水平。在此，我们表明，卵巢癌表现出过度应激UPS与正常组织相比，尽管蛋白酶体水平升高的泛素化蛋白的积累。在低级别和高级别卵巢癌组织中，相对于良性卵巢肿瘤，以及在卵巢癌细胞系中，相对于永生化表面上皮，总泛素化蛋白和19 S和20 S蛋白酶体亚基的水平升高是明显的。我们发现，卵巢癌细胞系表现出更大的敏感性，细胞凋亡的蛋白酶体抑制剂比永生化卵巢表面上皮细胞。这种敏感性与增加的细胞增殖率和UPS应激相关，而不是与绝对蛋白酶体水平相关。体外蛋白酶体抑制诱导细胞周期停滞和p21和p27的积累，并通过激活caspase-3触发细胞凋亡。此外，用许可的蛋白酶体抑制剂PS-341治疗可减缓免疫缺陷小鼠中ES-2卵巢癌异种移植物的生长。总之，上皮细胞恶性转化导致的增殖和代谢率升高使UPS应激，并使卵巢癌对蛋白酶体抑制引起的细胞凋亡更敏感。
The ubiquitin-proteasome system (UPS) mediates targeted protein degradation. Notably, the UPS determines levels of key checkpoint proteins controlling apoptosis and proliferation by controlling protein half-life. Herein, we show that ovarian carcinoma manifests an overstressed UPS by comparison with normal tissues by accumulation of ubiquitinated proteins despite elevated proteasome levels. Elevated levels of total ubiquitinated proteins and 19S and 20S proteasome subunits are evident in both low-grade and high-grade ovarian carcinoma tissues relative to benign ovarian tumors and in ovarian carcinoma cell lines relative to immortalized surface epithelium. We find that ovarian carcinoma cell lines exhibit greater sensitivity to apoptosis in response to proteasome inhibitors than immortalized ovarian surface epithelial cells. This sensitivity correlates with increased cellular proliferation rate and UPS stress rather than absolute proteasome levels. Proteasomal inhibition in vitro induces cell cycle arrest and the accumulation of p21 and p27 and triggers apoptosis via activation of caspase-3. Furthermore, treatment with the licensed proteasome inhibitor PS-341 slows the growth of ES-2 ovarian carcinoma xenograft in immunodeficient mice. In sum, elevated proliferation and metabolic rate resulting from malignant transformation of the epithelium stresses the UPS and renders ovarian carcinoma more sensitive to apoptosis in response to proteasomal inhibition.