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Inhibition of NUPR1-Karyopherin β1 Binding Increases Anticancer Drug Sensitivity

Authors
 Chanhee Park  ;  Jiwon Oh  ;  Won Mo Lee  ;  Hye Ran Koh  ;  Uy Dong Sohn  ;  Seung Wook Ham  ;  Kyungsoo Oh 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.22(6) : 2794, 2021-03 
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN
 1661-6596 
Issue Date
2021-03
MeSH
Acrylamides / chemistry ; Acrylamides / pharmacology* ; Active Transport, Cell Nucleus / drug effects ; Antibiotics, Antineoplastic / chemistry ; Antibiotics, Antineoplastic / pharmacology ; Basic Helix-Loop-Helix Transcription Factors / metabolism* ; Benzothiazoles / chemistry ; Benzothiazoles / pharmacology* ; Cell Line, Tumor ; Cell Nucleus / drug effects ; Cell Nucleus / metabolism ; Cell Survival / drug effects ; Doxorubicin / chemistry ; Doxorubicin / pharmacology* ; Drug Synergism ; Humans ; MCF-7 Cells ; Microscopy, Confocal ; Molecular Structure ; Neoplasm Proteins / metabolism* ; Protein Binding / drug effects ; beta Karyopherins / metabolism*
Keywords
KPNB1 ; NUPR1 ; combination ; drug sensitivity ; protein binding
Abstract
Background: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation.

Methods: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin β1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1-KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis.

Results: The single-molecule binding assay revealed that KPNB1 bound to NUPR1 with a binding affinity of 0.75 nM and that this binding was blocked by the aminothiazole ATZ-502. Following doxorubicin-only treatment, NUPR1 was translocated to the nucleus in more than 90% and NUPR1 translocation was blocked by the ATZ-502 combination treatment in MDA-MB-231 with no change in NUPR1 expression, providing strong evidence that NUPR1 nuclear translocation was directly inhibited by the ATZ-502 treatment. Inhibition of KPNB1 and NUPR1 binding was associated with a synergistic anticancer effect (up to 19.6-fold) in various cancer cell lines. NUPR1-related genes were also downregulated following the doxorubicin-ATZ-502 combination treatment.

Conclusion: Our current findings clearly demonstrate that NUPR1 translocation into the nucleus requires karyopherin β1 binding. Inhibition of the KPNB1 and NUPR1 interaction may constitute a new cancer therapeutic approach that can increase the drug efficacy while reducing the side effects.
DOI
10.3390/ijms22062794
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Park, Chan Hee(박찬희)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/191005
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