The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells
Received 24 April 2019
Accepted for publication 11 September 2019
Published 11 October 2019 Volume 2019:12 Pages 8387—8399
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Gaetano Romano
Reinhard Depping,1 Moritz von Fallois,1,2 Yosef Landesman,3 Friederike Katharina Kosyna1
1Center for Structural and Cell Biology in Medicine, Institute of Physiology, Working Group Hypoxia, University of Lübeck, Lübeck D-23562, Germany; 2Clinic for Radiotherapy, University Hospital Schleswig-Holstein, Lübeck D-23562, Germany; 3Karyopharm Therapeutics, Newton, MA, USA
Correspondence: Friederike Katharina Kosyna
Center for Structural and Cell Biology in Medicine, Institute of Physiology, Working Group Hypoxia, University of Lübeck, Ratzeburger Allee 160, Lübeck D-23562, Germany
Tel +49 451 3101 7322
Fax +49 451 3101 7304
Purpose: The nucleocytoplasmic transport of macromolecules is critical for both cell physiology and pathophysiology. Exportin 1 (XPO1), the major nuclear export receptor, is involved in the cellular adaptation to reduced oxygen availability by controlling the nuclear activity of the hypoxia-inducible factors (HIFs). Recently, a specific inhibitor of XPO1, selinexor (KPT-330), has been identified that inhibits nuclear export of cargo proteins by binding to the XPO1 cargo-binding pocket.
Patients and methods: We used different cancer cell lines from human tissues and evaluated the physiological activity of selinexor on the hypoxia response pathway in two-dimensional (2D) monolayer cell cultures in quantitative real-time (qRT)-PCR experiments and luciferase reporter gene assays. A three-dimensional (3D) tumor spheroid culture model of MCF-7 breast cancer cells was established to analyze the effect of selinexor on 3D tumor spheroid structure, formation and viability.
Results: Selinexor treatment reduces HIF-transcriptional activity and expression of the HIF-1 target gene solute carrier family 2 member 1 (SLC2A1). Moreover, 3D tumor spheroid structure, formation and viability are inhibited in response to selinexor-induced nuclear export inhibition.
Conclusion: Here, we demonstrate the effect of specific XPO1-inhibition on the hypoxic response on the molecular level in 2D and 3D culture models of MCF-7 cells.
Keywords: nuclear transport, HIF, hypoxia, XPO1, selinexor, tumor growth
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