The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells

• Main Authors: Depping R, von Fallois M, Landesman Y, Kosyna FK
• Format: Article
• Language: English
• Published: Dove Medical Press 2019-10-01
• Series: OncoTargets and Therapy
• Subjects: nuclear transport; HIF; hypoxia; XPO1; selinexor; tumor growth
• Online Access: https://www.dovepress.com/the-nuclear-export-inhibitor-selinexor-inhibits-hypoxia-signaling-path-peer-reviewed-article-OTT

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, USACorrespondence: Friederike Katharina KosynaCenter for Structural and Cell Biology in Medicine, Institute of Physiology, Working Group Hypoxia, University of Lübeck, Ratzeburger Allee 160, Lübeck D-23562, GermanyTel [phone]Fax [phone]Email [e-mail]: 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