Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment
Abstract TSC2, a suppressor of mTOR, is inactivated in up to 20% of HBV-associated liver cancer. This subtype of liver cancer is associated with aggressive behavior and early recurrence after hepatectomy. Being the first targeted regimen for advanced liver cancer, sorafenib has limited efficacy in H...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07332-6 |
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| author | Jiarui Lv Yanan Wang Jiacheng Lv Cuiting Zheng Xinyu Zhang Linyan Wan Jiayang Zhang Fangming Liu Hongbing Zhang |
| author_facet | Jiarui Lv Yanan Wang Jiacheng Lv Cuiting Zheng Xinyu Zhang Linyan Wan Jiayang Zhang Fangming Liu Hongbing Zhang |
| author_sort | Jiarui Lv |
| collection | DOAJ |
| description | Abstract TSC2, a suppressor of mTOR, is inactivated in up to 20% of HBV-associated liver cancer. This subtype of liver cancer is associated with aggressive behavior and early recurrence after hepatectomy. Being the first targeted regimen for advanced liver cancer, sorafenib has limited efficacy in HBV-positive patients. In this study, we observed that mTOR-activated cells, due to the loss of either TSC2 or PTEN, were insensitive to the treatment of sorafenib. Mechanistically, HSP70 enhanced the interaction between active mTOR-potentiated CREB1 and CREBBP to boost the transcription of the antioxidant response regulator SESN3. In return, elevated SESN3 enhanced cellular antioxidant capacity and rendered cells resistant to sorafenib. Pifithrin-μ, an HSP70 inhibitor, synergized with sorafenib in the induction of ferroptosis in mTOR-activated liver cancer cells and suppression of TSC2-deficient hepatocarcinogenesis. Our findings highlight the pivotal role of the mTOR-CREB1-SESN3 axis in sorafenib resistance of liver cancer and pave the way for combining pifithrin-μ and sorafenib for the treatment of mTOR-activated liver cancer. |
| format | Article |
| id | doaj-art-b4e5d3a31a55455b92fe833f23ae819b |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-b4e5d3a31a55455b92fe833f23ae819b2025-01-26T12:54:39ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111410.1038/s41419-025-07332-6Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatmentJiarui Lv0Yanan Wang1Jiacheng Lv2Cuiting Zheng3Xinyu Zhang4Linyan Wan5Jiayang Zhang6Fangming Liu7Hongbing Zhang8Department of Organ Transplantation and Hepatobiliary Surgery, Key Laboratory of Organ Transplantation of Liaoning Province, The First Hospital of China Medical UniversityDepartment of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Plastic Surgery, The First Hospital of China Medical UniversityDepartment of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and InstituteDepartment of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Organ Transplantation and Hepatobiliary Surgery, Key Laboratory of Organ Transplantation of Liaoning Province, The First Hospital of China Medical UniversityAbstract TSC2, a suppressor of mTOR, is inactivated in up to 20% of HBV-associated liver cancer. This subtype of liver cancer is associated with aggressive behavior and early recurrence after hepatectomy. Being the first targeted regimen for advanced liver cancer, sorafenib has limited efficacy in HBV-positive patients. In this study, we observed that mTOR-activated cells, due to the loss of either TSC2 or PTEN, were insensitive to the treatment of sorafenib. Mechanistically, HSP70 enhanced the interaction between active mTOR-potentiated CREB1 and CREBBP to boost the transcription of the antioxidant response regulator SESN3. In return, elevated SESN3 enhanced cellular antioxidant capacity and rendered cells resistant to sorafenib. Pifithrin-μ, an HSP70 inhibitor, synergized with sorafenib in the induction of ferroptosis in mTOR-activated liver cancer cells and suppression of TSC2-deficient hepatocarcinogenesis. Our findings highlight the pivotal role of the mTOR-CREB1-SESN3 axis in sorafenib resistance of liver cancer and pave the way for combining pifithrin-μ and sorafenib for the treatment of mTOR-activated liver cancer.https://doi.org/10.1038/s41419-025-07332-6 |
| spellingShingle | Jiarui Lv Yanan Wang Jiacheng Lv Cuiting Zheng Xinyu Zhang Linyan Wan Jiayang Zhang Fangming Liu Hongbing Zhang Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment Cell Death and Disease |
| title | Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment |
| title_full | Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment |
| title_fullStr | Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment |
| title_full_unstemmed | Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment |
| title_short | Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment |
| title_sort | pifithrin μ sensitizes mtor activated liver cancer to sorafenib treatment |
| url | https://doi.org/10.1038/s41419-025-07332-6 |
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