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Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer

BACKGROUND: Inhibition of nuclear import via Karyopherin beta 1 (Kpnβ1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. METHODS: Cervical cancer cells were pre-treated with INI-43 before treatment with ci...

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Autores principales: Chi, Ru-pin Alicia, van der Watt, Pauline, Wei, Wei, Birrer, Michael J., Leaner, Virna D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852134/
https://www.ncbi.nlm.nih.gov/pubmed/33530952
http://dx.doi.org/10.1186/s12885-021-07819-3
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author Chi, Ru-pin Alicia
van der Watt, Pauline
Wei, Wei
Birrer, Michael J.
Leaner, Virna D.
author_facet Chi, Ru-pin Alicia
van der Watt, Pauline
Wei, Wei
Birrer, Michael J.
Leaner, Virna D.
author_sort Chi, Ru-pin Alicia
collection PubMed
description BACKGROUND: Inhibition of nuclear import via Karyopherin beta 1 (Kpnβ1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. METHODS: Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NFκB was determined after co-treatment of cells. RESULTS: Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpnβ1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NFκB, which was diminished upon pre-treatment with INI-43. NFκB reporter activity and expression of NFκB transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. CONCLUSIONS: Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NFκB. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-07819-3.
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spelling pubmed-78521342021-02-03 Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer Chi, Ru-pin Alicia van der Watt, Pauline Wei, Wei Birrer, Michael J. Leaner, Virna D. BMC Cancer Research Article BACKGROUND: Inhibition of nuclear import via Karyopherin beta 1 (Kpnβ1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. METHODS: Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NFκB was determined after co-treatment of cells. RESULTS: Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpnβ1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NFκB, which was diminished upon pre-treatment with INI-43. NFκB reporter activity and expression of NFκB transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. CONCLUSIONS: Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NFκB. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-07819-3. BioMed Central 2021-02-02 /pmc/articles/PMC7852134/ /pubmed/33530952 http://dx.doi.org/10.1186/s12885-021-07819-3 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Chi, Ru-pin Alicia
van der Watt, Pauline
Wei, Wei
Birrer, Michael J.
Leaner, Virna D.
Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
title Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
title_full Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
title_fullStr Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
title_full_unstemmed Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
title_short Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
title_sort inhibition of kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852134/
https://www.ncbi.nlm.nih.gov/pubmed/33530952
http://dx.doi.org/10.1186/s12885-021-07819-3
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