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Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation.

Cell Chem Biol. 2017; 
Weyburne Emily S,Wilkins Owen M,Sha Zhe,Williams David A,Pletnev Alexandre A,de Bruin Gerjan,Overkleeft Hermann S,Goldberg Alfred L,Cole Michael D,Kisselev Alex
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Nucleic Acid Purification & Analysis for 20 min each at 37 C. Extracts were then fractionated on 10% Bis-Tris gels (Genscript) using MOPS Get A Quote

摘要

The proteasome inhibitors carfilzomib (Cfz) and bortezomib (Btz) are used successfully to treat multiple myeloma, but have not shown clinical efficacy in solid tumors. Here we show that clinically achievable inhibition of the β5 site of the proteasome by Cfz and Btz does not result in loss of viability of triple-negative breast cancer cell lines. We use site-specific inhibitors and CRISPR-mediated genetic inactivation of β1 and β2 to demonstrate that inhibiting a second site of the proteasome, particularly the β2 site, sensitizes cell lines to Btz and Cfz in?vitro and in?vivo. Inhibiting both β5 and β2 suppresses production of the soluble, active form of the transcription factor Nrf1 and prevents ... More

关键词

CRISPR,NFE2L1,Nrf1,bortezomib,carfilzomib,proteasome,triple-negative breast cancer,ubiqu