A tight balance of Karyopherin ß1 expression is required in cervical cancer cells.

BACKGROUND: Karyopherin ß1 (Kpnß1) is the main nuclear import protein involved in the transport of cargoes from the cytoplasm into the cell nucleus. Previous research has found Kpnß1 to be significantly overexpressed in cervical cancer and other cancer tissues, and further studies showed that inhibition of Kpnß1 expression by siRNA resulted in cancer cell death, while non-cancer cells were minimally affected. These results suggest that Kpnß1 has potential as an anticancer therapeutic target, thus warranting further research into the association between Kpnß1 expression and cancer progression. Here, the biological effects associated with Kpnß1 overexpression were investigated in order to further elucidate the relationship between Kpnß1 and the cancer phenotype. METHODS: To evaluate the effect of Kpnß1 overexpression on cell biology, cell proliferation, cell cycle, cell morphology and cell adhesion assays were performed. To determine whether Kpnß1 overexpression influences cell sensitivity to chemotherapeutic agents like Cisplatin, cell viability assays were performed. Expression levels of key proteins were analysed by Western blot analysis. RESULTS: Our data revealed that Kpnß1 overexpression, above that which was already detected in cancer cells, resulted in reduced proliferation of cervical cancer cells. Likewise, normal epithelial cells showed reduced proliferation after Kpnß1 overxpression. Reduced cancer cell proliferation was associated with a delay in cell cycle progression, as well as changes in the morphology and adhesion properties of cells. Additionally, Kpnß1 overexpressing HeLa cells exhibited increased sensitivity to cisplatin, as shown by decreased cell viability and increased apoptosis, where p53 and p21 inhibition reduced and enhanced cell sensitivity to Cisplatin, respectively. CONCLUSIONS: Overall, our results suggest that a tight balance of Kpnß1 expression is required for cellular function, and that perturbation of this balance results in negative effects associated with a variety of biological processes.

Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential.

The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets.

Targeting the Nuclear Import Receptor Kpnß1 as an Anticancer Therapeutic.

Karyopherin beta 1 (Kpnß1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnß1 expression was found in certain cancers and Kpnß1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnß1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnß1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpnß1 and known Kpnß1 cargoes NFAT, NFκB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of INI-43 that showed a significant cytotoxic effect on various cervical and esophageal cancer cell lines. A rescue experiment confirmed that INI-43 exerted its cell killing effects, in part, by targeting Kpnß1. INI-43 treatment elicited a G2-M cell-cycle arrest in cancer cells and induced the intrinsic apoptotic pathway. Intraperitoneal administration of INI-43 significantly inhibited the growth of subcutaneously xenografted esophageal and cervical tumor cells. We propose that Kpnß1 inhibitors could have therapeutic potential for the treatment of cancer. Mol Cancer Ther; 15(4); 560-73. ©2016 AACR.