Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, #SAMRC Gynaecology Cancer Research Centre, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa.
Department of Medicine, J.G. Brown Cancer Center, University of Louisville, Kentucky, USA.
Exp Cell Res. 2021 Jul 15;404(2):112637. doi: 10.1016/j.yexcr.2021.112637. Epub 2021 May 18.
Karyopherin beta 1 (Kpnβ1) is a major nuclear import receptor that mediates the import of cellular cargoes into the nucleus. Recently it has been shown that Kpnβ1 is highly expressed in several cancers, and its inhibition by siRNA induces apoptotic cancer cell death, while having little effect on non-cancer cells. This study investigated the effect of a novel small molecule, Inhibitor of Nuclear Import-60 (INI-60), on cancer cell biology, as well as nuclear import activities associated with Kpnβ1, and cancer progression in vivo using cervical and oesophageal cancer cell lines. INI-60 treatment resulted in the inhibition of cancer cell proliferation, colony formation, migration and invasion, and induced a G1/S cell cycle arrest, followed by cancer cell death via apoptosis. Non-cancer cells were minimally affected by INI-60 at concentrations that inhibited cancer cells. INI-60 treatment altered the localisation of Kpnβ1 and its cargoes, NFκB/p65, NFAT and AP-1, and the overexpression of Kpnβ1 reduced INI-60 cytotoxicity. INI-60 also inhibited KYSE 30 oesophageal cancer cell line growth in vivo. Taken together, these results show that INI-60 inhibits the nuclear import of Kpnβ1 cargoes and interferes with cancer cell biology. INI-60 presents as a potential therapeutic approach for cancers of different tissue origins and warrants further investigation as a novel anti-cancer agent.
核输入蛋白β 1（Kpnβ1）是一种主要的核输入受体，介导细胞货物进入细胞核。最近的研究表明，Kpnβ1 在几种癌症中高度表达，其通过 siRNA 抑制可诱导癌细胞凋亡死亡，而对非癌细胞影响很小。本研究使用宫颈和食管癌细胞系，研究了一种新型小分子 INI-60 对癌症细胞生物学以及与 Kpnβ1 相关的核输入活性和癌症进展的影响。INI-60 处理导致癌细胞增殖、集落形成、迁移和侵袭受到抑制，并诱导 G1/S 细胞周期停滞，随后通过细胞凋亡导致癌细胞死亡。非癌细胞在抑制癌细胞的浓度下受 INI-60 的影响最小。INI-60 处理改变了 Kpnβ1 及其货物 NFκB/p65、NFAT 和 AP-1 的定位，并且 Kpnβ1 的过表达降低了 INI-60 的细胞毒性。INI-60 还抑制了体内 KYSE 30 食管癌细胞系的生长。总之，这些结果表明 INI-60 抑制 Kpnβ1 货物的核输入，并干扰癌细胞生物学。INI-60 是一种有前途的治疗不同组织来源癌症的方法，值得进一步研究作为一种新型抗癌药物。
