The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer
Abstract 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 previousl...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05020-3 |
| _version_ | 1828336402377474048 |
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| author | Chengbo Ji Mili Zhang Junjie Hu Can Cao Qisheng Gu Youdong Liu Xu Li Duogang Xu Le Ying Yuqin Yang Hugh Gao Jikun Li Liang Yu |
| author_facet | Chengbo Ji Mili Zhang Junjie Hu Can Cao Qisheng Gu Youdong Liu Xu Li Duogang Xu Le Ying Yuqin Yang Hugh Gao Jikun Li Liang Yu |
| author_sort | Chengbo Ji |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T21:59:16Z |
| format | Article |
| id | doaj.art-74d9f8ed869647409e70b660ce9b88be |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T21:59:16Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-74d9f8ed869647409e70b660ce9b88be2022-12-22T02:28:08ZengNature Publishing GroupCell Death and Disease2041-48892022-07-0113711410.1038/s41419-022-05020-3The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancerChengbo Ji0Mili Zhang1Junjie Hu2Can Cao3Qisheng Gu4Youdong Liu5Xu Li6Duogang Xu7Le Ying8Yuqin Yang9Hugh Gao10Jikun Li11Liang Yu12Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineInstitut Pasteur of Shanghai, Chinese Academy of SciencesDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchDepartment of Laboratory Animal Centre, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash UniversityDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1038/s41419-022-05020-3 |
| spellingShingle | Chengbo Ji Mili Zhang Junjie Hu Can Cao Qisheng Gu Youdong Liu Xu Li Duogang Xu Le Ying Yuqin Yang Hugh Gao Jikun Li Liang Yu The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer Cell Death and Disease |
| 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 |
| url | https://doi.org/10.1038/s41419-022-05020-3 |
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