TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs
Abstract For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase in...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05577-7 |
| _version_ | 1797945713811783680 |
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| author | Chong Yang Xin Jin Xingchao Liu Gang Wu Wenhao Yang Beichuan Pang Jipeng Jiang Dongxu Liao Yu Zhang |
| author_facet | Chong Yang Xin Jin Xingchao Liu Gang Wu Wenhao Yang Beichuan Pang Jipeng Jiang Dongxu Liao Yu Zhang |
| author_sort | Chong Yang |
| collection | DOAJ |
| description | Abstract For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase inhibitors (TKIs), and the overall survival time of these patients is significantly increased. However, all responders ultimately develop resistance to TKI treatment. The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells. However, the biological role of TRIM15 in HCC is still an enigma. In our study, our results demonstrated that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells. Then, we demonstrated that the upregulation of TRIM15 after TKI treatment was mediated by the AKT/FOXO1 axis. Moreover, we demonstrated that TRIM15 induced the nuclear translocation of LASP1 by mediating its K63-linked polyubiquitination, which modulated sensitivity to TKIs by increasing the phosphorylation of AKT and the expression of Snail in liver cancer cells. Collectively, we identified a novel AKT/FOXO1/TRIM15/LASP1 loop in cells, which provided potential candidates for overcoming TKI resistance in HCC. |
| first_indexed | 2024-04-10T20:59:28Z |
| format | Article |
| id | doaj.art-ff2988e1febb4e6e93b80cc3a6d2915e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T20:59:28Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-ff2988e1febb4e6e93b80cc3a6d2915e2023-01-22T12:26:48ZengNature Publishing GroupCell Death and Disease2041-48892023-01-0114111310.1038/s41419-023-05577-7TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIsChong Yang0Xin Jin1Xingchao Liu2Gang Wu3Wenhao Yang4Beichuan Pang5Jipeng Jiang6Dongxu Liao7Yu Zhang8Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaDepartment of Urology, The Second Xiangya Hospital, Central South UniversityClinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaHepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaHepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaHepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaHepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaHepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaHepatobiliary and Pancreatic Surgery Department, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaAbstract For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase inhibitors (TKIs), and the overall survival time of these patients is significantly increased. However, all responders ultimately develop resistance to TKI treatment. The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells. However, the biological role of TRIM15 in HCC is still an enigma. In our study, our results demonstrated that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells. Then, we demonstrated that the upregulation of TRIM15 after TKI treatment was mediated by the AKT/FOXO1 axis. Moreover, we demonstrated that TRIM15 induced the nuclear translocation of LASP1 by mediating its K63-linked polyubiquitination, which modulated sensitivity to TKIs by increasing the phosphorylation of AKT and the expression of Snail in liver cancer cells. Collectively, we identified a novel AKT/FOXO1/TRIM15/LASP1 loop in cells, which provided potential candidates for overcoming TKI resistance in HCC.https://doi.org/10.1038/s41419-023-05577-7 |
| spellingShingle | Chong Yang Xin Jin Xingchao Liu Gang Wu Wenhao Yang Beichuan Pang Jipeng Jiang Dongxu Liao Yu Zhang TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs Cell Death and Disease |
| title | TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs |
| title_full | TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs |
| title_fullStr | TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs |
| title_full_unstemmed | TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs |
| title_short | TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs |
| title_sort | trim15 forms a regulatory loop with the akt foxo1 axis and lasp1 to modulate the sensitivity of hcc cells to tkis |
| url | https://doi.org/10.1038/s41419-023-05577-7 |
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