Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic
| Autor: | John O. Trent, Alicia Chi, Tamara Stelma, Dirk M. Lang, Michael J. Birrer, Erin Strydom, Virna D. Leaner, Sarah Carden, Pauline J. van der Watt, Wei Wei, Kate Hadley, Catherine L. Stowell, Liselotte Angus |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Models Molecular Cancer Research Cell Survival Gene Expression Antineoplastic Agents Apoptosis Bioinformatics Small Molecule Libraries 03 medical and health sciences Computers Molecular Mice Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Cytotoxic T cell Animals Humans Computer Simulation Molecular Targeted Therapy Receptor Cell Nucleus Chemistry Cancer NFAT medicine.disease beta Karyopherins Xenograft Model Antitumor Assays G2 Phase Cell Cycle Checkpoints Disease Models Animal Protein Transport 030104 developmental biology Cell killing Oncology Cell culture Cancer cell Cancer research Beta Karyopherins Female Protein Binding Transcription Factors |
| Zdroj: | Molecular cancer therapeutics. 15(4) |
| ISSN: | 1538-8514 |
| Popis: | Karyopherin beta 1 (Kpnβ1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnβ1 expression was found in certain cancers and Kpnβ1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnβ1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnβ1 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 Kpnβ1 and known Kpnβ1 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 Kpnβ1. 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 Kpnβ1 inhibitors could have therapeutic potential for the treatment of cancer. Mol Cancer Ther; 15(4); 560–73. ©2016 AACR. |
| Databáze: | OpenAIRE |
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