Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer
| dc.contributor.author | Chi, Ru-pin A | |
| dc.contributor.author | van der Watt, Pauline | |
| dc.contributor.author | Wei, Wei | |
| dc.contributor.author | Birrer, Michael J | |
| dc.contributor.author | Leaner, Virna D | |
| dc.date.accessioned | 2021-10-12T09:24:55Z | |
| dc.date.available | 2021-10-12T09:24:55Z | |
| dc.date.issued | 2021-02-02 | |
| dc.date.updated | 2021-02-07T04:12:54Z | |
| dc.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. | en_US |
| dc.identifier.apacitation | Chi, R. A., van der Watt, P., Wei, W., Birrer, M. J., & Leaner, V. D. (2021). Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer. <i>BMC Cancer</i>, 21(Article number: 106), http://hdl.handle.net/11427/35193 | en_ZA |
| dc.identifier.chicagocitation | Chi, Ru-pin A, Pauline van der Watt, Wei Wei, Michael J Birrer, and Virna D Leaner "Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer." <i>BMC Cancer</i> 21, Article number: 106. (2021) http://hdl.handle.net/11427/35193 | en_ZA |
| dc.identifier.citation | Chi, R.A., van der Watt, P., Wei, W., Birrer, M.J. & Leaner, V.D. 2021. Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer. <i>BMC Cancer.</i> 21(Article number: 106) http://hdl.handle.net/11427/35193 | en_ZA |
| dc.identifier.ris | TY - Journal Article AU - Chi, Ru-pin A AU - van der Watt, Pauline AU - Wei, Wei AU - Birrer, Michael J AU - Leaner, Virna D AB - 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. DA - 2021-02-02 DB - OpenUCT DP - University of Cape Town IS - Article number: 106 J1 - BMC Cancer KW - Cisplatin KW - INI-43 KW - Nuclear import KW - p53 KW - NFκB KW - Cervical cancer LK - https://open.uct.ac.za PY - 2021 T1 - Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer TI - Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer UR - http://hdl.handle.net/11427/35193 ER - | en_ZA |
| dc.identifier.uri | https://doi.org/10.1186/s12885-021-07819-3 | |
| dc.identifier.uri | http://hdl.handle.net/11427/35193 | |
| dc.identifier.vancouvercitation | Chi RA, van der Watt P, Wei W, Birrer MJ, Leaner VD. Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer. BMC Cancer. 2021;21(Article number: 106) http://hdl.handle.net/11427/35193. | en_ZA |
| dc.language.iso | en | en_US |
| dc.language.rfc3066 | en | |
| dc.publisher.department | Institute of Infectious Disease and Molecular Medicine | en_US |
| dc.publisher.faculty | Faculty of Health Sciences | en_US |
| dc.rights.holder | The Author(s) | |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
| dc.source | BMC Cancer | en_US |
| dc.source.journalissue | Article number: 106 | en_US |
| dc.source.journalvolume | 21 | en_US |
| dc.source.uri | https://bmccancer.biomedcentral.com/ | |
| dc.subject | Cisplatin | en_US |
| dc.subject | INI-43 | en_US |
| dc.subject | Nuclear import | en_US |
| dc.subject | p53 | en_US |
| dc.subject | NFκB | en_US |
| dc.subject | Cervical cancer | en_US |
| dc.title | Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer | en_US |
| dc.type | Journal Article | en_US |