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Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation
BACKGROUND: XPO1 mediates the nuclear export of several proteins, mainly tumor suppressors. KPT‐330 (Selinexor) is a selective inhibitor of XPO1 that has demonstrated good therapeutic effects in hematologic cancers. METHODS: We used TCGA and GTEx pan‐cancer database to evaluate XPO1 mRNA expression...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028126/ https://www.ncbi.nlm.nih.gov/pubmed/36200270 http://dx.doi.org/10.1002/cam4.5322 |
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author | Zhao, Cheng Ma, Ben Yang, Zi‐yi Li, Ou Liu, Shi‐lei Pan, Li‐jia Gong, Wei Dong, Ping Shu, Yi‐jun |
author_facet | Zhao, Cheng Ma, Ben Yang, Zi‐yi Li, Ou Liu, Shi‐lei Pan, Li‐jia Gong, Wei Dong, Ping Shu, Yi‐jun |
author_sort | Zhao, Cheng |
collection | PubMed |
description | BACKGROUND: XPO1 mediates the nuclear export of several proteins, mainly tumor suppressors. KPT‐330 (Selinexor) is a selective inhibitor of XPO1 that has demonstrated good therapeutic effects in hematologic cancers. METHODS: We used TCGA and GTEx pan‐cancer database to evaluate XPO1 mRNA expression in various tumors. Cell proliferation assay and colony formation assay were used to analyze the in vitro antitumor effects of XPO1 inhibitor KPT‐330. Western blot was performed to explore the specific mechanisms. RESULTS: We found that XPO1 was highly expressed across a range of cancers and associated with poor prognosis in hepatobiliary and pancreatic tumors. We revealed that the XPO1 inhibitor KPT‐330 triggered the nuclear accumulation of the p53 protein and significantly disrupted the proliferation of cholangiocarcinoma cells. Mechanistically, the XPO1 inhibitor, KPT‐330, reduced BIRC6 expression by inhibiting the PI3K/AKT pathway to decrease p53 degradation and improve its stability. CONCLUSION: Therefore, XPO1 may be a potential therapeutic target in cholangiocarcinoma, mediated by its effects on KPT‐330. |
format | Online Article Text |
id | pubmed-10028126 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100281262023-03-22 Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation Zhao, Cheng Ma, Ben Yang, Zi‐yi Li, Ou Liu, Shi‐lei Pan, Li‐jia Gong, Wei Dong, Ping Shu, Yi‐jun Cancer Med RESEARCH ARTICLES BACKGROUND: XPO1 mediates the nuclear export of several proteins, mainly tumor suppressors. KPT‐330 (Selinexor) is a selective inhibitor of XPO1 that has demonstrated good therapeutic effects in hematologic cancers. METHODS: We used TCGA and GTEx pan‐cancer database to evaluate XPO1 mRNA expression in various tumors. Cell proliferation assay and colony formation assay were used to analyze the in vitro antitumor effects of XPO1 inhibitor KPT‐330. Western blot was performed to explore the specific mechanisms. RESULTS: We found that XPO1 was highly expressed across a range of cancers and associated with poor prognosis in hepatobiliary and pancreatic tumors. We revealed that the XPO1 inhibitor KPT‐330 triggered the nuclear accumulation of the p53 protein and significantly disrupted the proliferation of cholangiocarcinoma cells. Mechanistically, the XPO1 inhibitor, KPT‐330, reduced BIRC6 expression by inhibiting the PI3K/AKT pathway to decrease p53 degradation and improve its stability. CONCLUSION: Therefore, XPO1 may be a potential therapeutic target in cholangiocarcinoma, mediated by its effects on KPT‐330. John Wiley and Sons Inc. 2022-10-05 /pmc/articles/PMC10028126/ /pubmed/36200270 http://dx.doi.org/10.1002/cam4.5322 Text en © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | RESEARCH ARTICLES Zhao, Cheng Ma, Ben Yang, Zi‐yi Li, Ou Liu, Shi‐lei Pan, Li‐jia Gong, Wei Dong, Ping Shu, Yi‐jun Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
title | Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
title_full | Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
title_fullStr | Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
title_full_unstemmed | Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
title_short | Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
title_sort | inhibition of xpo1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation |
topic | RESEARCH ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028126/ https://www.ncbi.nlm.nih.gov/pubmed/36200270 http://dx.doi.org/10.1002/cam4.5322 |
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