1. Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation.
- Author
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Weyburne ES, Wilkins OM, Sha Z, Williams DA, Pletnev AA, de Bruin G, Overkleeft HS, Goldberg AL, Cole MD, and Kisselev AF
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Nuclear Respiratory Factor 1 metabolism, Proteasome Inhibitors chemical synthesis, Proteasome Inhibitors chemistry, Structure-Activity Relationship, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Nuclear Respiratory Factor 1 antagonists & inhibitors, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors pharmacology, Triple Negative Breast Neoplasms drug therapy
- Abstract
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 the recovery of proteasome activity through induction of new proteasomes. These findings provide a strong rationale for the development of dual β5 and β2 inhibitors for the treatment of solid tumors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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