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- Title
Inhibition of NUPR1–Karyopherin β1 Binding Increases Anticancer Drug Sensitivity.
- Authors
Park, Chanhee; Oh, Jiwon; Lee, Won Mo; Koh, Hye Ran; Sohn, Uy Dong; Ham, Seung Wook; Oh, Kyungsoo; Quiles, José L.
- 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.
- Subjects
ANTINEOPLASTIC agents; BINDING site assay; DRUG efficacy; GENES; CELL cycle; GENE expression profiling
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 6, p2794
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22062794