Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
Abstract 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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-02-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-021-07819-3 |
| _version_ | 1819060144978264064 |
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| author | Ru-pin Alicia Chi Pauline van der Watt Wei Wei Michael J. Birrer Virna D. Leaner |
| author_facet | Ru-pin Alicia Chi Pauline van der Watt Wei Wei Michael J. Birrer Virna D. Leaner |
| author_sort | Ru-pin Alicia Chi |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-21T14:22:20Z |
| format | Article |
| id | doaj.art-c287017e64ab4882adcc441a246afb8b |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-21T14:22:20Z |
| publishDate | 2021-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-c287017e64ab4882adcc441a246afb8b2022-12-21T19:00:45ZengBMCBMC Cancer1471-24072021-02-0121111610.1186/s12885-021-07819-3Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancerRu-pin Alicia Chi0Pauline van der Watt1Wei Wei2Michael J. Birrer3Virna D. Leaner4Division of Medical Biochemistry & Structural Biology, Department of Integrative Biomedical Sciences, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, ObservatoryDivision of Medical Biochemistry & Structural Biology, Department of Integrative Biomedical Sciences, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, ObservatoryPfizerUniversity of Arkansas Medical Sciences, D Winthrop P. Rockefeller Cancer InstituteDivision of Medical Biochemistry & Structural Biology, Department of Integrative Biomedical Sciences, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, ObservatoryAbstract 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.https://doi.org/10.1186/s12885-021-07819-3CisplatinINI-43Nuclear importp53NFκBCervical cancer |
| spellingShingle | Ru-pin Alicia Chi Pauline van der Watt Wei Wei Michael J. Birrer Virna D. Leaner Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer BMC Cancer Cisplatin INI-43 Nuclear import p53 NFκB 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 | Cisplatin INI-43 Nuclear import p53 NFκB Cervical cancer |
| url | https://doi.org/10.1186/s12885-021-07819-3 |
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