Cargando…

NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer

Identifying cellular drivers responsible for enhancing cancer cell resistance to therapeutics provides critical information for designing more effective drugs. Populations of slowly growing, self-renewing, chemo-resistant cells purportedly contribute to the development of therapeutic resistance in m...

Descripción completa

Detalles Bibliográficos
Autores principales: Madajewski, Brian, Boatman, Michael A., Martinez, Ivan, Carter, Julia H., Bey, Erik A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047941/
https://www.ncbi.nlm.nih.gov/pubmed/36980879
http://dx.doi.org/10.3390/genes14030607
_version_ 1785014053669699584
author Madajewski, Brian
Boatman, Michael A.
Martinez, Ivan
Carter, Julia H.
Bey, Erik A.
author_facet Madajewski, Brian
Boatman, Michael A.
Martinez, Ivan
Carter, Julia H.
Bey, Erik A.
author_sort Madajewski, Brian
collection PubMed
description Identifying cellular drivers responsible for enhancing cancer cell resistance to therapeutics provides critical information for designing more effective drugs. Populations of slowly growing, self-renewing, chemo-resistant cells purportedly contribute to the development of therapeutic resistance in many solid tumors. In the current study, we implemented a tumor spheroid model to determine whether NAD(P)H quinone oxidoreductase-1 (NQO1) was requisite for self-renewal and promotion of the drug-resistant phenotype in non-small cell lung cancer (NSCLC). We found that stable depletion of NQO1 in A549 and H358 human NSCLC tumor models inhibits self-renewal capabilities, as demonstrated by a reduced ability to form primary, secondary, and tertiary spheroids. In contrast, the rescue of NQO1 expression restored the tumor cells’ ability to form spheroids. Additionally, we discovered that NQO1 depletion renders cisplatin-refractory tumor spheroids highly susceptible to drug treatment. Together, these results suggest that NQO1 loss reduces the self-renewing capabilities of NSCLC cells and enhances their susceptibility to clinically relevant therapeutics. These findings describe a novel role for NQO1 and suggest that combining NQO1-inhibitors with conventional chemotherapeutics may enhance anti-tumor effects.
format Online
Article
Text
id pubmed-10047941
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100479412023-03-29 NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer Madajewski, Brian Boatman, Michael A. Martinez, Ivan Carter, Julia H. Bey, Erik A. Genes (Basel) Article Identifying cellular drivers responsible for enhancing cancer cell resistance to therapeutics provides critical information for designing more effective drugs. Populations of slowly growing, self-renewing, chemo-resistant cells purportedly contribute to the development of therapeutic resistance in many solid tumors. In the current study, we implemented a tumor spheroid model to determine whether NAD(P)H quinone oxidoreductase-1 (NQO1) was requisite for self-renewal and promotion of the drug-resistant phenotype in non-small cell lung cancer (NSCLC). We found that stable depletion of NQO1 in A549 and H358 human NSCLC tumor models inhibits self-renewal capabilities, as demonstrated by a reduced ability to form primary, secondary, and tertiary spheroids. In contrast, the rescue of NQO1 expression restored the tumor cells’ ability to form spheroids. Additionally, we discovered that NQO1 depletion renders cisplatin-refractory tumor spheroids highly susceptible to drug treatment. Together, these results suggest that NQO1 loss reduces the self-renewing capabilities of NSCLC cells and enhances their susceptibility to clinically relevant therapeutics. These findings describe a novel role for NQO1 and suggest that combining NQO1-inhibitors with conventional chemotherapeutics may enhance anti-tumor effects. MDPI 2023-02-28 /pmc/articles/PMC10047941/ /pubmed/36980879 http://dx.doi.org/10.3390/genes14030607 Text en © 2023 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 Article
Madajewski, Brian
Boatman, Michael A.
Martinez, Ivan
Carter, Julia H.
Bey, Erik A.
NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer
title NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer
title_full NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer
title_fullStr NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer
title_full_unstemmed NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer
title_short NAD(P)H Quinone Oxidoreductase-1 Expression Promotes Self-Renewal and Therapeutic Resistance in Non-Small Cell Lung Cancer
title_sort nad(p)h quinone oxidoreductase-1 expression promotes self-renewal and therapeutic resistance in non-small cell lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047941/
https://www.ncbi.nlm.nih.gov/pubmed/36980879
http://dx.doi.org/10.3390/genes14030607
work_keys_str_mv AT madajewskibrian nadphquinoneoxidoreductase1expressionpromotesselfrenewalandtherapeuticresistanceinnonsmallcelllungcancer
AT boatmanmichaela nadphquinoneoxidoreductase1expressionpromotesselfrenewalandtherapeuticresistanceinnonsmallcelllungcancer
AT martinezivan nadphquinoneoxidoreductase1expressionpromotesselfrenewalandtherapeuticresistanceinnonsmallcelllungcancer
AT carterjuliah nadphquinoneoxidoreductase1expressionpromotesselfrenewalandtherapeuticresistanceinnonsmallcelllungcancer
AT beyerika nadphquinoneoxidoreductase1expressionpromotesselfrenewalandtherapeuticresistanceinnonsmallcelllungcancer