title: Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Weyburne
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Wilkins
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Sha
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Pletnev
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, 2333 CC Leiden, the Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: de Bruin
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, 2333 CC Leiden, the Netherlands.
authors.forename: Hermann S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Department of Genetics, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cole
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA. Electronic address: alexei.f.kisselev@gmail.com.
authors.forename: Alexei F
authors.initials: AF
authors.lastname: Kisselev
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051266:Nuclear Respiratory Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D061988:Proteasome Inhibitors; C561469:PSMB2 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: CRISPR; NFE2L1; Nrf1; bortezomib; carfilzomib; proteasome; triple-negative breast cancer; ubiquitin