Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC
Abstract T-LAK cell-oriented protein kinase (TOPK) is a potential therapeutic target in tumors. However, its role in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) has not been reported. Here, we found that TOPK was highly expressed in ALK-positive NSCLC. Additionally,...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05260-3 |
| _version_ | 1811201363192840192 |
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| author | Juanjuan Xiao Lu Zhang Huijun Yi Ling Zou Jianmei Mo Feng Xue Jinhua Zheng Yingze Huang Hui Lu Hansheng Wu Peipei Xue Xin Zhang Lifei He Zhaoxin Li Shigui Pang Guibin Qiao Qiuhong Duan Feng Zhu |
| author_facet | Juanjuan Xiao Lu Zhang Huijun Yi Ling Zou Jianmei Mo Feng Xue Jinhua Zheng Yingze Huang Hui Lu Hansheng Wu Peipei Xue Xin Zhang Lifei He Zhaoxin Li Shigui Pang Guibin Qiao Qiuhong Duan Feng Zhu |
| author_sort | Juanjuan Xiao |
| collection | DOAJ |
| description | Abstract T-LAK cell-oriented protein kinase (TOPK) is a potential therapeutic target in tumors. However, its role in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) has not been reported. Here, we found that TOPK was highly expressed in ALK-positive NSCLC. Additionally, ALK was identified as another upstream kinase of TOPK by in vitro kinase assay screening. Then, it was proven that ALK phosphorylated TOPK at Y74 in vitro and ex vivo, and the pathways downstream of ALK-TOPK were explored by phosphoproteomic analysis. Subsequently, we demonstrated that inhibiting TOPK enhanced tumor sensitivity to alectinib (an ALK inhibitor). The combination of alectinib and HI-032 (a TOPK inhibitor) suppressed the growth and promoted the apoptosis of ALK-positive NSCLC cells ex vivo and in vivo. Our findings reveal a novel ALK-TOPK signaling pathway in ALK-positive NSCLC. The combination of alectinib and HI-032 might be a promising therapeutic strategy for improving the sensitivity of ALK-positive NSCLC to targeted therapy. |
| first_indexed | 2024-04-12T02:20:37Z |
| format | Article |
| id | doaj.art-f1471ee8df014544b6641d6825d4a76c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T02:20:37Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-f1471ee8df014544b6641d6825d4a76c2022-12-22T03:52:08ZengNature Publishing GroupCell Death and Disease2041-48892022-09-0113911010.1038/s41419-022-05260-3Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLCJuanjuan Xiao0Lu Zhang1Huijun Yi2Ling Zou3Jianmei Mo4Feng Xue5Jinhua Zheng6Yingze Huang7Hui Lu8Hansheng Wu9Peipei Xue10Xin Zhang11Lifei He12Zhaoxin Li13Shigui Pang14Guibin Qiao15Qiuhong Duan16Feng Zhu17Cancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityThe Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People’s Hospital)Cancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and TechnologyCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityDepartment of Oncology, The Affiliated Hospital of Guilin Medical UniversityDepartment of Pathology, The Affiliated Hospital of Guilin Medical UniversityCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityWuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Thoracic Surgery, The first affiliated hospital of Shanton University Medical CollegeNHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research InstituteDepartment of Oncology, The Affiliated Hospital of Guilin Medical UniversityCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityDepartment of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical SciencesDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and TechnologyCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityAbstract T-LAK cell-oriented protein kinase (TOPK) is a potential therapeutic target in tumors. However, its role in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) has not been reported. Here, we found that TOPK was highly expressed in ALK-positive NSCLC. Additionally, ALK was identified as another upstream kinase of TOPK by in vitro kinase assay screening. Then, it was proven that ALK phosphorylated TOPK at Y74 in vitro and ex vivo, and the pathways downstream of ALK-TOPK were explored by phosphoproteomic analysis. Subsequently, we demonstrated that inhibiting TOPK enhanced tumor sensitivity to alectinib (an ALK inhibitor). The combination of alectinib and HI-032 (a TOPK inhibitor) suppressed the growth and promoted the apoptosis of ALK-positive NSCLC cells ex vivo and in vivo. Our findings reveal a novel ALK-TOPK signaling pathway in ALK-positive NSCLC. The combination of alectinib and HI-032 might be a promising therapeutic strategy for improving the sensitivity of ALK-positive NSCLC to targeted therapy.https://doi.org/10.1038/s41419-022-05260-3 |
| spellingShingle | Juanjuan Xiao Lu Zhang Huijun Yi Ling Zou Jianmei Mo Feng Xue Jinhua Zheng Yingze Huang Hui Lu Hansheng Wu Peipei Xue Xin Zhang Lifei He Zhaoxin Li Shigui Pang Guibin Qiao Qiuhong Duan Feng Zhu Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC Cell Death and Disease |
| title | Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC |
| title_full | Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC |
| title_fullStr | Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC |
| title_full_unstemmed | Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC |
| title_short | Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC |
| title_sort | inhibiting alk topk signaling pathway promotes cell apoptosis of alk positive nsclc |
| url | https://doi.org/10.1038/s41419-022-05260-3 |
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