The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity.


Journal

Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639

Informations de publication

Date de publication:
05 2022
Historique:
received: 15 02 2022
revised: 09 03 2022
accepted: 15 03 2022
pubmed: 22 3 2022
medline: 20 4 2022
entrez: 21 3 2022
Statut: ppublish

Résumé

The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.

Identifiants

pubmed: 35313207
pii: S2213-2317(22)00063-5
doi: 10.1016/j.redox.2022.102291
pmc: PMC8938334
pii:
doi:

Substances chimiques

Kelch-Like ECH-Associated Protein 1 0
NF-E2-Related Factor 2 0
Triterpenes 0
Oleanolic Acid 6SMK8R7TGJ
bardoxolone 7HT68L8941

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

102291

Subventions

Organisme : Cancer Research UK
ID : C52419/A22869
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C20953/A18644
Pays : United Kingdom

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Auteurs

Laura Casares (L)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK.

Rita Moreno (R)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK.

Kevin X Ali (KX)

Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.

Maureen Higgins (M)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK.

Sharadha Dayalan Naidu (S)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK.

Graham Neill (G)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK.

Lena Cassin (L)

Department of Biomedicine, Health, Aarhus University, 8000, Denmark.

Anders E Kiib (AE)

Department of Chemistry, Aarhus University, Denmark.

Esben B Svenningsen (EB)

Department of Chemistry, Aarhus University, Denmark.

Alberto Minassi (A)

Department of Drug Science, University of Piemonte Orientale, Novara, Italy.

Tadashi Honda (T)

Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, 11794-3400, USA.

Thomas B Poulsen (TB)

Department of Chemistry, Aarhus University, Denmark.

Clotilde Wiel (C)

Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.

Volkan I Sayin (VI)

Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.

Albena T Dinkova-Kostova (AT)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK.

David Olagnier (D)

Department of Biomedicine, Health, Aarhus University, 8000, Denmark.

Laureano de la Vega (L)

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, UK. Electronic address: l.delavega@dundee.ac.uk.

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Classifications MeSH