Abstract B12: Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells

Abstract

Abstract Karyopherin β1 (Kpnβ1) is the major nuclear import protein involved in the shuttling of cargo proteins and mRNAs into the cell nucleus. Recent studies have found that Kpnβ1 levels are significantly upregulated in cancer cells, and that targeted inhibition of Kpnβ1 with siRNA results in reduced proliferation and the induction of apoptosis, suggesting that Kpnβ1 is important for cancer cell survival. Inhibitor of Nuclear Import-43 (INI-43) is a small molecule inhibitor identified in our laboratory as having the potential to interfere with the nuclear import function of Kpnβ1. It has been shown to inhibit the nuclear localization of both Kpnβ1 and known Kpnβ1 cargoes such as NFκB and NFAT, as well as inhibit the proliferation of cancer cells of different tissue origins. This study aimed to investigate the specificity of INI-43 for Kpnβ1 by performing experiments to determine whether expression of exogenous Kpnβ1-GFP was able to rescue cells from the effects of INI-43 treatment. Results show that Kpnβ1 overexpression rescues cell viability, as well as the inhibitory effects that INI-43 has on the nuclear import of NFκB/p65 and NFAT. Overexpression of Kpnβ1 also rescues cells from an INI-43 induced G2/M cell cycle block. In addition, treatment of cells with INI-43 enhances degradation of Kpnβ1, but not of other members of the Karyopherin family. These results suggest that the small molecule inhibitor INI-43 is acting, at least in part, by targeting Kpnβ1. Citation Format: Sarah Carden, Pauline van der Watt, Patrizia Lavia, Virna Leaner. Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B12.