Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line

Abstract Hyperactivation of ABC transporter ABCB1 and induction of epithelial–mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisit...

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Autores principales: Raimonda Kubiliute, Indre Januskeviciene, Ruta Urbanaviciute, Kristina Daniunaite, Monika Drobniene, Valerijus Ostapenko, Rimantas Daugelavicius, Sonata Jarmalaite
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Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/b0cfe9885eb14543aa4eed855fbd4b5b
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spelling oai:doaj.org-article:b0cfe9885eb14543aa4eed855fbd4b5b2021-12-02T14:02:53ZNongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line10.1038/s41598-021-86120-62045-2322https://doaj.org/article/b0cfe9885eb14543aa4eed855fbd4b5b2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86120-6https://doaj.org/toc/2045-2322Abstract Hyperactivation of ABC transporter ABCB1 and induction of epithelial–mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.Raimonda KubiliuteIndre JanuskevicieneRuta UrbanaviciuteKristina DaniunaiteMonika DrobnieneValerijus OstapenkoRimantas DaugelaviciusSonata JarmalaiteNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Raimonda Kubiliute
Indre Januskeviciene
Ruta Urbanaviciute
Kristina Daniunaite
Monika Drobniene
Valerijus Ostapenko
Rimantas Daugelavicius
Sonata Jarmalaite
Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line
description Abstract Hyperactivation of ABC transporter ABCB1 and induction of epithelial–mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.
format article
author Raimonda Kubiliute
Indre Januskeviciene
Ruta Urbanaviciute
Kristina Daniunaite
Monika Drobniene
Valerijus Ostapenko
Rimantas Daugelavicius
Sonata Jarmalaite
author_facet Raimonda Kubiliute
Indre Januskeviciene
Ruta Urbanaviciute
Kristina Daniunaite
Monika Drobniene
Valerijus Ostapenko
Rimantas Daugelavicius
Sonata Jarmalaite
author_sort Raimonda Kubiliute
title Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line
title_short Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line
title_full Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line
title_fullStr Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line
title_full_unstemmed Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line
title_sort nongenotoxic abcb1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in mx-1 breast cancer cell line
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/b0cfe9885eb14543aa4eed855fbd4b5b
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