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Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic.
Mol Cancer Ther. 2016 04; 15(4):560-73.MC

Abstract

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.

Authors+Show Affiliations

Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Confocal and Light Microscope Imaging Facility, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.Center for Cancer Research, The Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Center for Cancer Research, The Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.Department of Medicine, J.G. Brown Cancer Center, University of Louisville, Louisville, Kentucky.Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. Virna.Leaner@uct.ac.za.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26832790

Citation

van der Watt, Pauline J., et al. "Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic." Molecular Cancer Therapeutics, vol. 15, no. 4, 2016, pp. 560-73.
van der Watt PJ, Chi A, Stelma T, et al. Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic. Mol Cancer Ther. 2016;15(4):560-73.
van der Watt, P. J., Chi, A., Stelma, T., Stowell, C., Strydom, E., Carden, S., Angus, L., Hadley, K., Lang, D., Wei, W., Birrer, M. J., Trent, J. O., & Leaner, V. D. (2016). Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic. Molecular Cancer Therapeutics, 15(4), 560-73. https://doi.org/10.1158/1535-7163.MCT-15-0052
van der Watt PJ, et al. Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic. Mol Cancer Ther. 2016;15(4):560-73. PubMed PMID: 26832790.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic. AU - van der Watt,Pauline J, AU - Chi,Alicia, AU - Stelma,Tamara, AU - Stowell,Catherine, AU - Strydom,Erin, AU - Carden,Sarah, AU - Angus,Liselotte, AU - Hadley,Kate, AU - Lang,Dirk, AU - Wei,Wei, AU - Birrer,Michael J, AU - Trent,John O, AU - Leaner,Virna D, Y1 - 2016/02/01/ PY - 2015/01/20/received PY - 2016/01/15/accepted PY - 2016/2/3/entrez PY - 2016/2/3/pubmed PY - 2017/6/16/medline SP - 560 EP - 73 JF - Molecular cancer therapeutics JO - Mol Cancer Ther VL - 15 IS - 4 N2 - 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. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/26832790/full_citation L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=26832790 DB - PRIME DP - Unbound Medicine ER -