Selinexor decreases HIF-1α via inhibition of CRM1 in human osteosarcoma and hepatoma cells associated with an increased radiosensitivity.
Apoptosis
Bone Neoplasms
/ drug therapy
Carcinoma, Hepatocellular
/ drug therapy
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Hydrazines
/ pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit
/ antagonists & inhibitors
Karyopherins
/ antagonists & inhibitors
Liver Neoplasms
/ drug therapy
Osteosarcoma
/ drug therapy
Radiation Tolerance
/ drug effects
Radiation-Sensitizing Agents
/ pharmacology
Receptors, Cytoplasmic and Nuclear
/ antagonists & inhibitors
Triazoles
/ pharmacology
Tumor Cells, Cultured
Exportin 1 Protein
CRM1
HIF
Hypoxia
Nuclear transport
Radiotherapy
Selinexor
Journal
Journal of cancer research and clinical oncology
ISSN: 1432-1335
Titre abrégé: J Cancer Res Clin Oncol
Pays: Germany
ID NLM: 7902060
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
13
01
2021
accepted:
30
03
2021
pubmed:
16
4
2021
medline:
8
6
2021
entrez:
15
4
2021
Statut:
ppublish
Résumé
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. 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. 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. Targeting the HIF pathway by Selinexor might be an attractive tool to overcome hypoxia-induced radioresistance.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
Targeting the HIF pathway by Selinexor might be an attractive tool to overcome hypoxia-induced radioresistance.
Identifiants
pubmed: 33856525
doi: 10.1007/s00432-021-03626-2
pii: 10.1007/s00432-021-03626-2
pmc: PMC8164574
doi:
Substances chimiques
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
0
selinexor
31TZ62FO8F
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2025-2033Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : KO5512/2-1
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