PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer

Resistance to PARP inhibitors (PARPi) remains a therapeutic challenge in ovarian cancer patients. PDZ-binding kinase (PBK) participates in the chemoresistance of many malignancies. However, the role of PBK in PARPi resistance of ovarian cancer is obscure. In the current study, we demonstrated that o...

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Autores principales: Ma, Hanlin, Qi, Gonghua, Han, Fang, Peng, Jiali, Yuan, Cunzhong, Kong, Beihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355941/
https://www.ncbi.nlm.nih.gov/pubmed/35859118
http://dx.doi.org/10.1038/s12276-022-00809-w
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author Ma, Hanlin
Qi, Gonghua
Han, Fang
Peng, Jiali
Yuan, Cunzhong
Kong, Beihua
author_facet Ma, Hanlin
Qi, Gonghua
Han, Fang
Peng, Jiali
Yuan, Cunzhong
Kong, Beihua
author_sort Ma, Hanlin
collection PubMed
description Resistance to PARP inhibitors (PARPi) remains a therapeutic challenge in ovarian cancer patients. PDZ-binding kinase (PBK) participates in the chemoresistance of many malignancies. However, the role of PBK in PARPi resistance of ovarian cancer is obscure. In the current study, we demonstrated that overexpression of PBK contributed to olaparib resistance in ovarian cancer cells. Knockdown of PBK sensitized olaparib-resistant SKOV3 cells to olaparib. Inhibition of PBK using a specific inhibitor enhanced the therapeutic efficiency of olaparib. Mechanically, PBK directly interacted with TRIM37 to promote its phosphorylation and nuclear translocation. which subsequently activates the NFκB pathway. Additionally, PBK enhanced olaparib resistance of ovarian cancer by regulating the NFκB/TRIM37 axis in vitro and in vivo. In conclusion, PBK confers ovarian cancer resistance to PARPi through activating the TRIM37-mediated NFκB pathway, and targeted inhibition of PBK provided the new therapy to improve PARPi treatment outcomes for ovarian cancer patients.
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spelling pubmed-93559412022-08-19 PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer Ma, Hanlin Qi, Gonghua Han, Fang Peng, Jiali Yuan, Cunzhong Kong, Beihua Exp Mol Med Article Resistance to PARP inhibitors (PARPi) remains a therapeutic challenge in ovarian cancer patients. PDZ-binding kinase (PBK) participates in the chemoresistance of many malignancies. However, the role of PBK in PARPi resistance of ovarian cancer is obscure. In the current study, we demonstrated that overexpression of PBK contributed to olaparib resistance in ovarian cancer cells. Knockdown of PBK sensitized olaparib-resistant SKOV3 cells to olaparib. Inhibition of PBK using a specific inhibitor enhanced the therapeutic efficiency of olaparib. Mechanically, PBK directly interacted with TRIM37 to promote its phosphorylation and nuclear translocation. which subsequently activates the NFκB pathway. Additionally, PBK enhanced olaparib resistance of ovarian cancer by regulating the NFκB/TRIM37 axis in vitro and in vivo. In conclusion, PBK confers ovarian cancer resistance to PARPi through activating the TRIM37-mediated NFκB pathway, and targeted inhibition of PBK provided the new therapy to improve PARPi treatment outcomes for ovarian cancer patients. Nature Publishing Group UK 2022-07-20 /pmc/articles/PMC9355941/ /pubmed/35859118 http://dx.doi.org/10.1038/s12276-022-00809-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ma, Hanlin
Qi, Gonghua
Han, Fang
Peng, Jiali
Yuan, Cunzhong
Kong, Beihua
PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
title PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
title_full PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
title_fullStr PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
title_full_unstemmed PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
title_short PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
title_sort pbk drives parp inhibitor resistance through the trim37/nfκb axis in ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355941/
https://www.ncbi.nlm.nih.gov/pubmed/35859118
http://dx.doi.org/10.1038/s12276-022-00809-w
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