AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription
Abstract Purpose This study aimed to investigate that AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer (GC) progression via targeted regulation of IRS-1 transcription. Methods The study utilized databases such as PhosphositePlus, TRANSFAC, CHEA, GPS 5.0, and TCGA, along with experimental...
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| Language: | English |
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Springer
2024-12-01
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| Series: | Journal of Cancer Research and Clinical Oncology |
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| Online Access: | https://doi.org/10.1007/s00432-024-06039-z |
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| author | Lingshan Zhou Yuan Yang Qian Qiao Yingying Mi Yuling Gan Ya Zheng Yuping Wang Min Liu Yongning Zhou |
| author_facet | Lingshan Zhou Yuan Yang Qian Qiao Yingying Mi Yuling Gan Ya Zheng Yuping Wang Min Liu Yongning Zhou |
| author_sort | Lingshan Zhou |
| collection | DOAJ |
| description | Abstract Purpose This study aimed to investigate that AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer (GC) progression via targeted regulation of IRS-1 transcription. Methods The study utilized databases such as PhosphositePlus, TRANSFAC, CHEA, GPS 5.0, and TCGA, along with experimental techniques including Western Blot, co-IP, in vitro kinase assay, construction of lentiviral overexpression and silencing vectors, immunoprecipitation, modified proteomics, immunofluorescence, ChIP-PCR, EdU assay, Transwell assay, and scratch assay to investigate the effects of AKT1-induced Notch1 phosphorylation on cell proliferation, invasion and migration in vitro, as well as growth and epithelial-mesenchymal transition (EMT) in vivo. Results AKT1 was found to induce phosphorylation of Notch1 at the S2183 site in GC, subsequently altering the subcellular localization of Notch1-IC and promoting its nuclear translocation. The transcription factor RBPJ that binds to Notch1 transcriptionally regulated IRS-1, CDH5, TNL1, ASCL2, and LRP6. Experimental validation revealed that Notch1-IC can regulate the expression of IRS-1. Overexpression of Notch1-IC was shown to promote the proliferation, invasion, and metastasis of GC cells, while knockdown of IRS-1 partially inhibited the aforementioned effects induced by Notch1-IC overexpression. Further experiments in vitro and vivo confirmed that AKT1-induced Notch1 phosphorylation can regulate the expression of IRS-1 and promote the malignant behavior of GC, including proliferation, invasion, metastasis, and EMT, with knockdown of IRS-1 partially reversing these effects. Conclusion AKT1 induces the Notch1 phosphorylation and promotes the activation and nuclear translocation of Notch1-IC by targeting the regulation of IRS-1, thereby advancing the progression of GC. |
| format | Article |
| id | doaj-art-c184066a1cf249dbb8878cc3cd0b8987 |
| institution | Kabale University |
| issn | 1432-1335 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer |
| record_format | Article |
| series | Journal of Cancer Research and Clinical Oncology |
| spelling | doaj-art-c184066a1cf249dbb8878cc3cd0b89872025-02-09T12:10:24ZengSpringerJournal of Cancer Research and Clinical Oncology1432-13352024-12-01151111310.1007/s00432-024-06039-zAKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcriptionLingshan Zhou0Yuan Yang1Qian Qiao2Yingying Mi3Yuling Gan4Ya Zheng5Yuping Wang6Min Liu7Yongning Zhou8The First Clinical Medical College, Lanzhou UniversityDepartment of Gastroenterology, The First Affiliated Hospital, Hengyang Medical School, University of South ChinaThe First Clinical Medical College, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityThe 1nd Department of Bone and Soft Tissue Oncology, Gansu Provincial Cancer HospitalThe First Clinical Medical College, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityAbstract Purpose This study aimed to investigate that AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer (GC) progression via targeted regulation of IRS-1 transcription. Methods The study utilized databases such as PhosphositePlus, TRANSFAC, CHEA, GPS 5.0, and TCGA, along with experimental techniques including Western Blot, co-IP, in vitro kinase assay, construction of lentiviral overexpression and silencing vectors, immunoprecipitation, modified proteomics, immunofluorescence, ChIP-PCR, EdU assay, Transwell assay, and scratch assay to investigate the effects of AKT1-induced Notch1 phosphorylation on cell proliferation, invasion and migration in vitro, as well as growth and epithelial-mesenchymal transition (EMT) in vivo. Results AKT1 was found to induce phosphorylation of Notch1 at the S2183 site in GC, subsequently altering the subcellular localization of Notch1-IC and promoting its nuclear translocation. The transcription factor RBPJ that binds to Notch1 transcriptionally regulated IRS-1, CDH5, TNL1, ASCL2, and LRP6. Experimental validation revealed that Notch1-IC can regulate the expression of IRS-1. Overexpression of Notch1-IC was shown to promote the proliferation, invasion, and metastasis of GC cells, while knockdown of IRS-1 partially inhibited the aforementioned effects induced by Notch1-IC overexpression. Further experiments in vitro and vivo confirmed that AKT1-induced Notch1 phosphorylation can regulate the expression of IRS-1 and promote the malignant behavior of GC, including proliferation, invasion, metastasis, and EMT, with knockdown of IRS-1 partially reversing these effects. Conclusion AKT1 induces the Notch1 phosphorylation and promotes the activation and nuclear translocation of Notch1-IC by targeting the regulation of IRS-1, thereby advancing the progression of GC.https://doi.org/10.1007/s00432-024-06039-zGastric cancerNotch1 phosphorylationAKT1IRS-1Inhibition |
| spellingShingle | Lingshan Zhou Yuan Yang Qian Qiao Yingying Mi Yuling Gan Ya Zheng Yuping Wang Min Liu Yongning Zhou AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription Journal of Cancer Research and Clinical Oncology Gastric cancer Notch1 phosphorylation AKT1 IRS-1 Inhibition |
| title | AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription |
| title_full | AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription |
| title_fullStr | AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription |
| title_full_unstemmed | AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription |
| title_short | AKT1-Mediated NOTCH1 phosphorylation promotes gastric cancer progression via targeted regulation of IRS-1 transcription |
| title_sort | akt1 mediated notch1 phosphorylation promotes gastric cancer progression via targeted regulation of irs 1 transcription |
| topic | Gastric cancer Notch1 phosphorylation AKT1 IRS-1 Inhibition |
| url | https://doi.org/10.1007/s00432-024-06039-z |
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