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Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells

Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necrop...

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Autores principales: Zhou, Huiling, Zhou, Li, Guan, Qing, Hou, Xuyang, Wang, Cong, Liu, Lijun, Wang, Jian, Yu, Xinfang, Li, Wei, Liu, Haidan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10397346/
https://www.ncbi.nlm.nih.gov/pubmed/37532777
http://dx.doi.org/10.1038/s42003-023-05166-6
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author Zhou, Huiling
Zhou, Li
Guan, Qing
Hou, Xuyang
Wang, Cong
Liu, Lijun
Wang, Jian
Yu, Xinfang
Li, Wei
Liu, Haidan
author_facet Zhou, Huiling
Zhou, Li
Guan, Qing
Hou, Xuyang
Wang, Cong
Liu, Lijun
Wang, Jian
Yu, Xinfang
Li, Wei
Liu, Haidan
author_sort Zhou, Huiling
collection PubMed
description Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant NSCLC cells. Accordingly, inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin in vitro and in vivo. Mechanistically, Skp2 interacts and promotes ubiquitination-mediated degradation of MLKL in cisplatin-resistant NSCLC cells. Our results provide evidence of an Skp2-dependent mechanism regulating MLKL degradation and cisplatin resistance, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance.
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spelling pubmed-103973462023-08-04 Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells Zhou, Huiling Zhou, Li Guan, Qing Hou, Xuyang Wang, Cong Liu, Lijun Wang, Jian Yu, Xinfang Li, Wei Liu, Haidan Commun Biol Article Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant NSCLC cells. Accordingly, inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin in vitro and in vivo. Mechanistically, Skp2 interacts and promotes ubiquitination-mediated degradation of MLKL in cisplatin-resistant NSCLC cells. Our results provide evidence of an Skp2-dependent mechanism regulating MLKL degradation and cisplatin resistance, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance. Nature Publishing Group UK 2023-08-02 /pmc/articles/PMC10397346/ /pubmed/37532777 http://dx.doi.org/10.1038/s42003-023-05166-6 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/) .
spellingShingle Article
Zhou, Huiling
Zhou, Li
Guan, Qing
Hou, Xuyang
Wang, Cong
Liu, Lijun
Wang, Jian
Yu, Xinfang
Li, Wei
Liu, Haidan
Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
title Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
title_full Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
title_fullStr Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
title_full_unstemmed Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
title_short Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
title_sort skp2-mediated mlkl degradation confers cisplatin-resistant in non-small cell lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10397346/
https://www.ncbi.nlm.nih.gov/pubmed/37532777
http://dx.doi.org/10.1038/s42003-023-05166-6
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