Cargando…
The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer
The activity of integrin-linked kinase (ILK) in cancerous cells is often oncogenic and associated with malignant properties, such as uncontrolled cell cycle progression and evasion from senescence. However, the role of ILK in cellular senescence in gastric cancer (GC) has not been previously examine...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249761/ https://www.ncbi.nlm.nih.gov/pubmed/35778385 http://dx.doi.org/10.1038/s41419-022-05020-3 |
_version_ | 1784739658149658624 |
---|---|
author | Ji, Chengbo Zhang, Mili Hu, Junjie Cao, Can Gu, Qisheng Liu, Youdong Li, Xu Xu, Duogang Ying, Le Yang, Yuqin Gao, Hugh Li, Jikun Yu, Liang |
author_facet | Ji, Chengbo Zhang, Mili Hu, Junjie Cao, Can Gu, Qisheng Liu, Youdong Li, Xu Xu, Duogang Ying, Le Yang, Yuqin Gao, Hugh Li, Jikun Yu, Liang |
author_sort | Ji, Chengbo |
collection | PubMed |
description | The activity of integrin-linked kinase (ILK) in cancerous cells is often oncogenic and associated with malignant properties, such as uncontrolled cell cycle progression and evasion from senescence. However, the role of ILK in cellular senescence in gastric cancer (GC) has not been previously examined. We generated single-cell clones of ILK knock-out using CRISPR-Cas9 in human GC lines with mesenchymal or epithelial histology. Cells with no residual ILK expression exhibited strong cellular senescence with diminished clathrin-mediated endocytosis, Surprisingly, ILK loss-induced cellular senescence appeared to be independent of its function in integrin signaling. The low dose of CPD22, a small molecule inhibitor of ILK activity-induced senescence in three GC cell lines with different histologies. Furthermore, senescent cells with ILK depletion transfected with N-terminal truncated ILK mutant remaining catalytic domains displayed the reduction of senescent phenotypes. RNA sequencing and cytokine array results revealed the enrichment of multiple pro-inflammatory signaling pathways in GC lines in the absence of ILK. Our study identified the important role and the potential mechanism of ILK in the cellular senescence of cancerous epithelial cells. The inhibition of ILK activity using small molecule compounds could have a pro-senescent effect as a therapeutic option for GC. |
format | Online Article Text |
id | pubmed-9249761 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92497612022-07-03 The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer Ji, Chengbo Zhang, Mili Hu, Junjie Cao, Can Gu, Qisheng Liu, Youdong Li, Xu Xu, Duogang Ying, Le Yang, Yuqin Gao, Hugh Li, Jikun Yu, Liang Cell Death Dis Article The activity of integrin-linked kinase (ILK) in cancerous cells is often oncogenic and associated with malignant properties, such as uncontrolled cell cycle progression and evasion from senescence. However, the role of ILK in cellular senescence in gastric cancer (GC) has not been previously examined. We generated single-cell clones of ILK knock-out using CRISPR-Cas9 in human GC lines with mesenchymal or epithelial histology. Cells with no residual ILK expression exhibited strong cellular senescence with diminished clathrin-mediated endocytosis, Surprisingly, ILK loss-induced cellular senescence appeared to be independent of its function in integrin signaling. The low dose of CPD22, a small molecule inhibitor of ILK activity-induced senescence in three GC cell lines with different histologies. Furthermore, senescent cells with ILK depletion transfected with N-terminal truncated ILK mutant remaining catalytic domains displayed the reduction of senescent phenotypes. RNA sequencing and cytokine array results revealed the enrichment of multiple pro-inflammatory signaling pathways in GC lines in the absence of ILK. Our study identified the important role and the potential mechanism of ILK in the cellular senescence of cancerous epithelial cells. The inhibition of ILK activity using small molecule compounds could have a pro-senescent effect as a therapeutic option for GC. Nature Publishing Group UK 2022-07-01 /pmc/articles/PMC9249761/ /pubmed/35778385 http://dx.doi.org/10.1038/s41419-022-05020-3 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 Ji, Chengbo Zhang, Mili Hu, Junjie Cao, Can Gu, Qisheng Liu, Youdong Li, Xu Xu, Duogang Ying, Le Yang, Yuqin Gao, Hugh Li, Jikun Yu, Liang The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
title | The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
title_full | The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
title_fullStr | The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
title_full_unstemmed | The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
title_short | The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
title_sort | kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249761/ https://www.ncbi.nlm.nih.gov/pubmed/35778385 http://dx.doi.org/10.1038/s41419-022-05020-3 |
work_keys_str_mv | AT jichengbo thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT zhangmili thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT hujunjie thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT caocan thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT guqisheng thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT liuyoudong thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT lixu thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT xuduogang thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT yingle thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT yangyuqin thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT gaohugh thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT lijikun thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT yuliang thekinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT jichengbo kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT zhangmili kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT hujunjie kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT caocan kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT guqisheng kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT liuyoudong kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT lixu kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT xuduogang kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT yingle kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT yangyuqin kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT gaohugh kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT lijikun kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer AT yuliang kinaseactivityofintegrinlinkedkinaseregulatescellularsenescenceingastriccancer |