Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies
Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, m...
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| Language: | English |
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Elsevier
2024-11-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524001652 |
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| author | Liang-Yun Chen Dao-Sian Wu Yao-An Shen |
| author_facet | Liang-Yun Chen Dao-Sian Wu Yao-An Shen |
| author_sort | Liang-Yun Chen |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. To specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs’ characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC. |
| format | Article |
| id | doaj-art-5f535f9ec85b4b25aba8ca11a88b4e09 |
| institution | DOAJ |
| issn | 0022-2275 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-5f535f9ec85b4b25aba8ca11a88b4e092025-08-20T02:48:45ZengElsevierJournal of Lipid Research0022-22752024-11-01651110066010.1016/j.jlr.2024.100660Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategiesLiang-Yun Chen0Dao-Sian Wu1Yao-An Shen2Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanDepartment of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanDepartment of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; For correspondence: Yao-An ShenHepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. To specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs’ characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC.http://www.sciencedirect.com/science/article/pii/S0022227524001652cancer stem cellliver cancerfatty acid metabolismcombination therapyamyloid precursor protein |
| spellingShingle | Liang-Yun Chen Dao-Sian Wu Yao-An Shen Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies Journal of Lipid Research cancer stem cell liver cancer fatty acid metabolism combination therapy amyloid precursor protein |
| title | Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies |
| title_full | Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies |
| title_fullStr | Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies |
| title_full_unstemmed | Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies |
| title_short | Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies |
| title_sort | fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through fasn app axis as novel therapeutic strategies |
| topic | cancer stem cell liver cancer fatty acid metabolism combination therapy amyloid precursor protein |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524001652 |
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