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

Senthil K. Radhakrishnan,Ajay Potluri,Janakiram R. Vangala

doi:10.3390/biom10040501

Senthil K. Radhakrishnan, Ajay Potluri + Show 1 more

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https://doi.org/10.3390/biom10040501

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Journal: Biomolecules	Publication Date: Mar 26, 2020
Citations: 18	License type: CC BY 4.0

Affiliation: Virginia Commonwealth University

Abstract

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.

Highlights

The ubiquitin-proteasome system (UPS) is a major quality control pathway in eukaryotic cells and is responsible for selective and timely removal of proteins that are destined for destruction [1]
Using carfilzomib (CFZ), ixazomib-citrate (IXA), and bortezomib (BTZ) as input drugs in SynergySeq, we observed that various bromodomain extra-terminal (BET) inhibitors such as I-BET151, JQ1, I-BET762, and PFI1 emerged as potential synergistic interactors with proteasome inhibitors (Figure 1A)
We found several optimal CFZ + BET inhibitor combinations that were highly synergistic in the T98G cell line (Figure 1B; first panel)

Summary

Introduction

The ubiquitin-proteasome system (UPS) is a major quality control pathway in eukaryotic cells and is responsible for selective and timely removal of proteins that are destined for destruction [1]. The 19S regulatory particle caps at one or both ends of the 20S proteasome and enables the recognition and transfer of ubiquitinated target proteins to the 20S catalytic core for degradation [3]. Proliferating cells such as cancer cells have an increased reliance on proteasome activity [4]. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, have been approved by the FDA for clinical use against multiple myeloma (MM) and mantle cell lymphoma (MCL). The events downstream of β5 inhibition that lead to cancer cell death are not completely understood

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