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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00524767" target="_blank" >RIV/61388963:_____/20:00524767 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/20:10411382 RIV/00216208:11310/20:10411382

Result on the web

<a href="https://www.mdpi.com/2072-6694/12/5/1065" target="_blank" >https://www.mdpi.com/2072-6694/12/5/1065</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/cancers12051065" target="_blank" >10.3390/cancers12051065</a>

Result language

angličtina

Original language name

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

Original language 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cancers (Basel)

ISSN

2072-6694

e-ISSN

—

Volume of the periodical

12

Issue of the periodical within the volume

5

Country of publishing house

CH - SWITZERLAND

Number of pages

17

Pages from-to

1065

UT code for WoS article

000539246000006

EID of the result in the Scopus database

2-s2.0-85084070624