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PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway
BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells. METHODS: The ATdb...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10633943/ https://www.ncbi.nlm.nih.gov/pubmed/37940999 http://dx.doi.org/10.1186/s13046-023-02823-w |
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author | Zheng, Fang Zhong, Jiamin Chen, Kelie Shi, Yu Wang, Fang Wang, Shengchao Tang, Song Yuan, Xiaoyu Shen, Zhangjin Tang, Sangsang Xia, Dajing Wu, Yihua Lu, Weiguo |
author_facet | Zheng, Fang Zhong, Jiamin Chen, Kelie Shi, Yu Wang, Fang Wang, Shengchao Tang, Song Yuan, Xiaoyu Shen, Zhangjin Tang, Sangsang Xia, Dajing Wu, Yihua Lu, Weiguo |
author_sort | Zheng, Fang |
collection | PubMed |
description | BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells. METHODS: The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice. RESULTS: PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells’ ability to resist chemotherapy and metastasize. CONCLUSIONS: PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02823-w. |
format | Online Article Text |
id | pubmed-10633943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106339432023-11-10 PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway Zheng, Fang Zhong, Jiamin Chen, Kelie Shi, Yu Wang, Fang Wang, Shengchao Tang, Song Yuan, Xiaoyu Shen, Zhangjin Tang, Sangsang Xia, Dajing Wu, Yihua Lu, Weiguo J Exp Clin Cancer Res Research BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells. METHODS: The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice. RESULTS: PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells’ ability to resist chemotherapy and metastasize. CONCLUSIONS: PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02823-w. BioMed Central 2023-11-09 /pmc/articles/PMC10633943/ /pubmed/37940999 http://dx.doi.org/10.1186/s13046-023-02823-w Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zheng, Fang Zhong, Jiamin Chen, Kelie Shi, Yu Wang, Fang Wang, Shengchao Tang, Song Yuan, Xiaoyu Shen, Zhangjin Tang, Sangsang Xia, Dajing Wu, Yihua Lu, Weiguo PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
title | PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
title_full | PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
title_fullStr | PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
title_full_unstemmed | PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
title_short | PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
title_sort | pink1-pten axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10633943/ https://www.ncbi.nlm.nih.gov/pubmed/37940999 http://dx.doi.org/10.1186/s13046-023-02823-w |
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