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The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study

Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) protein is the master regulator of oxidative stress, which is at the basis of various chronic diseases including cancer. Hyperactivation of NRF2 in already established cancers can promote cell proliferation and resistance to therapies, s...

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Autores principales: Garufi, Alessia, Pistritto, Giuseppa, D’Orazi, Valerio, Cirone, Mara, D’Orazi, Gabriella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946796/
https://www.ncbi.nlm.nih.gov/pubmed/35327653
http://dx.doi.org/10.3390/biom12030461
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author Garufi, Alessia
Pistritto, Giuseppa
D’Orazi, Valerio
Cirone, Mara
D’Orazi, Gabriella
author_facet Garufi, Alessia
Pistritto, Giuseppa
D’Orazi, Valerio
Cirone, Mara
D’Orazi, Gabriella
author_sort Garufi, Alessia
collection PubMed
description Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) protein is the master regulator of oxidative stress, which is at the basis of various chronic diseases including cancer. Hyperactivation of NRF2 in already established cancers can promote cell proliferation and resistance to therapies, such as in colorectal cancer (CRC), one of the most lethal and prevalent malignancies in industrialized countries with limited patient overall survival due to its escape mechanisms in both chemo- and targeted therapies. In this study, we generated stable NRF2 knockout colon cancer cells (NRF2-Cas9) to investigate the cell response to chemotherapeutic drugs with regard to p53 oncosuppressor, whose inhibition we previously showed to correlate with NRF2 pathway activation. Here, we found that NRF2 activation by sulforaphane (SFN) reduced cisplatin (CDDP)-induced cell death only in NRF2-proficient cells (NRF2-ctr) compared to NRF2-Cas9 cells. Mechanistically, we found that NRF2 activation protected NRF2-ctr cells from the drug-induced DNA damage and the apoptotic function of the unfolded protein response (UPR), in correlation with reduction of p53 activity, effects that were not observed in NRF2-Cas9 cells. Finally, we found that ZnCl(2) supplementation rescued the cisplatin cytotoxic effects, as it impaired NRF2 activation, restoring p53 activity. These findings highlight NRF2′s key role in neutralizing the cytotoxic effects of chemotherapeutic drugs in correlation with reduced DNA damage and p53 activity. They also suggest that NRF2 inhibition could be a useful strategy for efficient anticancer chemotherapy and support the use of ZnCl(2) to inhibit NRF2 pathway in combination therapies.
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spelling pubmed-89467962022-03-25 The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study Garufi, Alessia Pistritto, Giuseppa D’Orazi, Valerio Cirone, Mara D’Orazi, Gabriella Biomolecules Communication Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) protein is the master regulator of oxidative stress, which is at the basis of various chronic diseases including cancer. Hyperactivation of NRF2 in already established cancers can promote cell proliferation and resistance to therapies, such as in colorectal cancer (CRC), one of the most lethal and prevalent malignancies in industrialized countries with limited patient overall survival due to its escape mechanisms in both chemo- and targeted therapies. In this study, we generated stable NRF2 knockout colon cancer cells (NRF2-Cas9) to investigate the cell response to chemotherapeutic drugs with regard to p53 oncosuppressor, whose inhibition we previously showed to correlate with NRF2 pathway activation. Here, we found that NRF2 activation by sulforaphane (SFN) reduced cisplatin (CDDP)-induced cell death only in NRF2-proficient cells (NRF2-ctr) compared to NRF2-Cas9 cells. Mechanistically, we found that NRF2 activation protected NRF2-ctr cells from the drug-induced DNA damage and the apoptotic function of the unfolded protein response (UPR), in correlation with reduction of p53 activity, effects that were not observed in NRF2-Cas9 cells. Finally, we found that ZnCl(2) supplementation rescued the cisplatin cytotoxic effects, as it impaired NRF2 activation, restoring p53 activity. These findings highlight NRF2′s key role in neutralizing the cytotoxic effects of chemotherapeutic drugs in correlation with reduced DNA damage and p53 activity. They also suggest that NRF2 inhibition could be a useful strategy for efficient anticancer chemotherapy and support the use of ZnCl(2) to inhibit NRF2 pathway in combination therapies. MDPI 2022-03-17 /pmc/articles/PMC8946796/ /pubmed/35327653 http://dx.doi.org/10.3390/biom12030461 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Garufi, Alessia
Pistritto, Giuseppa
D’Orazi, Valerio
Cirone, Mara
D’Orazi, Gabriella
The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study
title The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study
title_full The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study
title_fullStr The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study
title_full_unstemmed The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study
title_short The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study
title_sort impact of nrf2 inhibition on drug-induced colon cancer cell death and p53 activity: a pilot study
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946796/
https://www.ncbi.nlm.nih.gov/pubmed/35327653
http://dx.doi.org/10.3390/biom12030461
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