Cargando…

Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma

Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the...

Descripción completa

Detalles Bibliográficos
Autores principales: Fassmannová, Dominika, Sedlák, František, Sedláček, Jindřich, Špička, Ivan, Grantz Šašková, Klára
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281108/
https://www.ncbi.nlm.nih.gov/pubmed/32344880
http://dx.doi.org/10.3390/cancers12051065
_version_ 1783543845388025856
author Fassmannová, Dominika
Sedlák, František
Sedláček, Jindřich
Špička, Ivan
Grantz Šašková, Klára
author_facet Fassmannová, Dominika
Sedlák, František
Sedláček, Jindřich
Špička, Ivan
Grantz Šašková, Klára
author_sort Fassmannová, Dominika
collection PubMed
description Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir’s effectiveness in the treatment of multiple myeloma.
format Online
Article
Text
id pubmed-7281108
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72811082020-06-15 Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma Fassmannová, Dominika Sedlák, František Sedláček, Jindřich Špička, Ivan Grantz Šašková, Klára Cancers (Basel) Article Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir’s effectiveness in the treatment of multiple myeloma. MDPI 2020-04-25 /pmc/articles/PMC7281108/ /pubmed/32344880 http://dx.doi.org/10.3390/cancers12051065 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fassmannová, Dominika
Sedlák, František
Sedláček, Jindřich
Špička, Ivan
Grantz Šašková, Klára
Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma
title Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma
title_full Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma
title_fullStr Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma
title_full_unstemmed Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma
title_short Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma
title_sort nelfinavir inhibits the tcf11/nrf1-mediated proteasome recovery pathway in multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281108/
https://www.ncbi.nlm.nih.gov/pubmed/32344880
http://dx.doi.org/10.3390/cancers12051065
work_keys_str_mv AT fassmannovadominika nelfinavirinhibitsthetcf11nrf1mediatedproteasomerecoverypathwayinmultiplemyeloma
AT sedlakfrantisek nelfinavirinhibitsthetcf11nrf1mediatedproteasomerecoverypathwayinmultiplemyeloma
AT sedlacekjindrich nelfinavirinhibitsthetcf11nrf1mediatedproteasomerecoverypathwayinmultiplemyeloma
AT spickaivan nelfinavirinhibitsthetcf11nrf1mediatedproteasomerecoverypathwayinmultiplemyeloma
AT grantzsaskovaklara nelfinavirinhibitsthetcf11nrf1mediatedproteasomerecoverypathwayinmultiplemyeloma