Selinexor decreases HIF-1α via inhibition of CRM1 in human osteosarcoma and hepatoma cells associated with an increased radiosensitivity.

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Abstrakt

Tytuł:: Selinexor decreases HIF-1α via inhibition of CRM1 in human osteosarcoma and hepatoma cells associated with an increased radiosensitivity.
Autorzy:: von Fallois M; Universität Zu Lübeck, Institut Für Physiologie, Working Group Hypoxia, Ratzeburger Allee 160, 23562, Lübeck, Germany.
Kosyna FK; Universität Zu Lübeck, Institut Für Physiologie, Working Group Hypoxia, Ratzeburger Allee 160, 23562, Lübeck, Germany.
Mandl M; Universität Zu Lübeck, Institut Für Physiologie, Working Group Hypoxia, Ratzeburger Allee 160, 23562, Lübeck, Germany.
Landesman Y; Karyopharm Therapeutics, 85 Wells Ave, Newton, MA, 02459, USA.
Dunst J; Universitätsklinikum Schleswig-Holstein, Campus Kiel-Klinik für Strahlentherapie, Arnold-Heller-Straße 3, 24105, Kiel, Germany.
Depping R; Universität Zu Lübeck, Institut Für Physiologie, Working Group Hypoxia, Ratzeburger Allee 160, 23562, Lübeck, Germany. .
Źródło:: Journal of cancer research and clinical oncology [J Cancer Res Clin Oncol] 2021 Jul; Vol. 147 (7), pp. 2025-2033. Date of Electronic Publication: 2021 Apr 15.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Berlin ; New York : Springer-Verlag.
MeSH Terms:: Carcinoma, Hepatocellular/*radiotherapy
Hydrazines/*pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors
Karyopherins/*antagonists & inhibitors
Osteosarcoma/*radiotherapy
Radiation Tolerance/*drug effects
Radiation-Sensitizing Agents/*pharmacology
Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors
Triazoles/*pharmacology
Apoptosis ; Bone Neoplasms/drug therapy ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Bone Neoplasms/radiotherapy ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Karyopherins/genetics ; Karyopherins/metabolism ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Liver Neoplasms/radiotherapy ; Osteosarcoma/drug therapy ; Osteosarcoma/metabolism ; Osteosarcoma/pathology ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Tumor Cells, Cultured ; Exportin 1 Protein
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Grant Information:: KO5512/2-1 Deutsche Forschungsgemeinschaft
Contributed Indexing:: Keywords: CRM1; HIF; Hypoxia; Nuclear transport; Radiotherapy; Selinexor
Substance Nomenclature:: 0 (HIF1A protein, human)
0 (Hydrazines)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (Karyopherins)
0 (Radiation-Sensitizing Agents)
0 (Receptors, Cytoplasmic and Nuclear)
0 (Triazoles)
31TZ62FO8F (selinexor)
Entry Date(s):: Date Created: 20210415 Date Completed: 20210607 Latest Revision: 20231213
Update Code:: 20240104
PubMed Central ID:: PMC8164574
DOI:: 10.1007/s00432-021-03626-2
PMID:: 33856525
: Czasopismo naukowe

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Background: The nuclear pore complexes (NPCs) are built of about 30 different nucleoporins and act as key regulators of molecular traffic between the cytoplasm and the nucleus for sizeable proteins (> 40 kDa) which must enter the nucleus. Various nuclear transport receptors are involved in import and export processes of proteins through the nuclear pores. The most prominent nuclear export receptor is chromosome region maintenance 1 (CRM1), also known as exportin 1 (XPO1). One of its cargo proteins is the prolyl hydroxylase 2 (PHD2) which is involved in the initiation of the degradation of hypoxia-inducible factors (HIFs) under normoxia. HIFs are proteins that regulate the cellular adaptation under hypoxic conditions. They are involved in many aspects of cell viability and play an important role in the hypoxic microenvironment of cancer. In cancer, CRM1 is often overexpressed thus being a putative target for the development of new cancer therapies. The newly FDA-approved pharmaceutical Selinexor (KPT-330) selectively inhibits nuclear export via CRM1 and is currently tested in additional Phase-III clinical trials. In this study, we investigated the effect of CRM1 inhibition on the subcellular localization of HIF-1α and radiosensitivity.
Methods: Human hepatoma cells Hep3B and human osteosarcoma cells U2OS were treated with Selinexor. Intranuclear concentration of HIF-1α protein was measured using immunoblot analysis. Furthermore, cells were irradiated with 2-8 Gy after treatment with Selinexor compared to untreated controls.
Results: Selinexor significantly reduced the intranuclear level of HIF-1α protein in human hepatoma cells Hep3B and human osteosarcoma cells U2OS. Moreover, we demonstrated by clonogenic survival assays that Selinexor leads to dose-dependent radiosensitization in Hep3B-hepatoma and U2OS-osteosarcoma cells.
Conclusion: Targeting the HIF pathway by Selinexor might be an attractive tool to overcome hypoxia-induced radioresistance.

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