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Inhibition of Kpn?1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer.
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ABSTRACT: Background
Inhibition of nuclear import via Karyopherin beta 1 (Kpn?1) 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 NF?B 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. Kpn?1 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 NF?B, which was diminished upon pre-treatment with INI-43. NF?B reporter activity and expression of NF?B 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 NF?B. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer.
SUBMITTER: Chi RA
PROVIDER: S-EPMC7852134 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer.
BMC cancer 20210202 1
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Pre-treatment of cervi ...[more]