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Open AccessArticle

BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response

Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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Author to whom correspondence should be addressed.
Biomolecules 2020, 10(4), 501; https://doi.org/10.3390/biom10040501
Received: 10 February 2020 / Revised: 21 March 2020 / Accepted: 24 March 2020 / Published: 26 March 2020
(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)
Currently, proteasome inhibitors bortezomib, carfilzomib, and ixazomib are successfully used in clinics to treat multiple myeloma. However, these agents show limited efficacy against solid tumors. Identification of drugs that can potentiate the action of proteasome inhibitors could help expand the use of this therapeutic modality to solid tumors. Here, we found that bromodomain extra-terminal (BET) family protein inhibitors such as JQ1, I-BET762, and I-BET151 synergize with carfilzomib in multiple solid tumor cell lines. Mechanistically, BET inhibitors attenuated the ability of the transcription factor Nrf1 to induce proteasome genes in response to proteasome inhibition, thus, impeding the bounce-back response of proteasome activity, a critical pathway by which cells cope with proteotoxic stress. Moreover, we found that treatment with BET inhibitors or depletion of Nrf1 exacerbated the unfolded protein response (UPR), signaling that was initiated by proteasome inhibition. Taken together, our work provides a mechanistic explanation behind the synergy between proteasome and BET inhibitors in cancer cell lines and could prompt future preclinical and clinical studies aimed at further investigating this combination. View Full-Text
Keywords: BET inhibitors; Nrf1; proteasome genes; transcription; proteasome inhibitor; cancer; unfolded protein response BET inhibitors; Nrf1; proteasome genes; transcription; proteasome inhibitor; cancer; unfolded protein response
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Vangala, J.R.; Potluri, A.; Radhakrishnan, S.K. BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response. Biomolecules 2020, 10, 501.

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