Depleting the 19S proteasome regulatory PSMD1 subunit as a cancer therapy strategy

被引:2
作者
Adler, Julia [1 ]
Oren, Roni [2 ]
Shaul, Yosef [1 ,3 ]
机构
[1] Weizmann Inst Sci, Dept Mol Genet, Rehovot, Israel
[2] Weizmann Inst Sci, Dept Vet Resources, Rehovot, Israel
[3] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel
来源
CANCER MEDICINE | 2023年 / 12卷 / 09期
关键词
19S regulatory particle; 26S proteasome; breast cancer; cancer therapy; mouse xenografts; ovarian cancer PDX; INHIBITORS;
D O I
10.1002/cam4.5775
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundProteasome inhibitors are in use in treating certain types of cancers. These drugs inhibit the catalytic activity of the 20S proteasome, shared by all the different proteasome complexes. Inhibitors of the 26S-associated deubiquitinating activity explicitly inhibit the 26S proteasomal degradation of ubiquitinylated substrates. We have previously reported an alternative strategy that is based on reducing the 26S/20S ratio by depleting PSMD1, 6, and 11, the subunits of the 19S proteasome regulatory complex. Given the addiction of the many cancer types to a high 26S/20S ratio, the depletion strategy is highly effective in killing many aggressive cancer cell lines but not mouse and human immortalized and normal cells. MethodsWe used two aggressive cell lines, MDA-MB-231, a triple-negative breast tumor cell line, and OVCAR8, a high-grade ovary adenocarcinoma. Cell culture, mouse MDA-MB-231, OVCAR8 xenografts, and patient-derived ovarian cancer xenograft (PDX) models were transduced with lentivectors expressing PSMD1 shRNA. Tumor size was measured to follow treatment efficacy. ResultsUsing different experimental strategies of expressing shRNA, we found that PSMD1 depletion, either by expressing PSMD1 shRNA in an inducible manner or in a constitutive manner, robustly inhibited MDA-MB-231, and OVCAR8 xenograft tumor growth. Furthermore, the PSMD1 depletion strategy compromised the growth of the PDX of primary ovarian cancer. ConclusionOur results suggest that reducing the 26S/20S ratio might be a valuable strategy for treating drug-resistant aggressive types of cancers.
引用
收藏
页码:10781 / 10790
页数:10
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