KPNB1-mediated nuclear import is required for motility and inflammatory transcription factor activity in cervical cancer cells.

Karyopherin ß1 is a nuclear import protein involved in the transport of proteins containing a nuclear localisation sequence. Elevated Karyopherin ß1 expression has been reported in cancer and transformed cells and is essential for cancer cell proliferation and survival. Transcription factors such as NFĸB and AP-1 contain a nuclear localisation sequence and initiate the expression of multiple factors associated with inflammation and cancer cell biology. Our study investigated the effect of inhibiting nuclear import via Karyopherin ß1 on cancer cell motility and inflammatory signaling using siRNA and the novel small molecule, Inhibitor of Nuclear Import-43, INI-43. Inhibition of Karyopherin ß1 led to reduced migration and invasion of cervical cancer cells. Karyopherin ß1 is essential for the translocation of NFĸB into the nucleus as nuclear import inhibition caused its cytoplasmic retention and decreased transcriptional activity. A similar decrease was seen in AP-1 transcriptional activity upon Karyopherin ß1 inhibition. Consequently reduced interleukin-6, interleukin-1 beta, tumour necrosis factor alpha and granulocyte macrophage colony stimulating factor expression, target genes of NFkB and AP-1, was observed. Migration studies inhibiting individual transcription factors suggested that INI-43 may affect a combination of signaling events. Our study provides further evidence that inhibiting KPNB1 has anti-cancer effects and shows promise as a chemotherapeutic target.

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.