SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth
Abstract Renal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03999-9 |
| _version_ | 1818648319668256768 |
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| author | Tong-bing Wang Mei Geng Hua Jin Ai-guo Tang Hao Sun Liu-zheng Zhou Bin-hai Chen Gang Shen Qiang Sun |
| author_facet | Tong-bing Wang Mei Geng Hua Jin Ai-guo Tang Hao Sun Liu-zheng Zhou Bin-hai Chen Gang Shen Qiang Sun |
| author_sort | Tong-bing Wang |
| collection | DOAJ |
| description | Abstract Renal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor. We here tested its activity in RCC cells. In established and primary human RCC cells, PF-429242 potently inhibited cell proliferation, migration, and invasion. The S1P inhibitor provoked apoptosis activation in RCC cells. Furthermore, shRNA-mediated S1P silencing or CRISPR/Cas9-induced S1P knockout led to RCC cell growth inhibition and apoptosis activation. Conversely, ectopic overexpression of SREBP1 or S1P augmented RCC cell proliferation and migration. Daily i.v. injection of a single dose of PF-429242 robustly inhibited RCC xenograft growth in severe combined immunodeficiency mice. Additionally, intratumoral injection of S1P shRNA lentivirus inhibited RCC xenograft growth in mice. SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo. |
| first_indexed | 2024-12-17T01:16:33Z |
| format | Article |
| id | doaj.art-91a402a328784f37bc4909b49438acc7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-17T01:16:33Z |
| publishDate | 2021-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-91a402a328784f37bc4909b49438acc72022-12-21T22:08:58ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112811110.1038/s41419-021-03999-9SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growthTong-bing Wang0Mei Geng1Hua Jin2Ai-guo Tang3Hao Sun4Liu-zheng Zhou5Bin-hai Chen6Gang Shen7Qiang Sun8Department of Urology, People’s Hospital of Yangzhong CityDepartment of Oncology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineThe Child Health Care Department, Suzhou Ninth People’s HospitalDepartment of Urology, The affiliated Hospital of Jiangsu UniversityDepartment of Urology, The affiliated Hospital of Jiangsu UniversityDepartment of Urology, The affiliated Hospital of Jiangsu UniversityDepartment of Urology, The affiliated Hospital of Jiangsu UniversityDepartment of Urology, DUSHU Lake Hospital Affiliated to Soochow UniversityDepartment of Nephrology, Affiliated Kunshan Hospital of Jiangsu UniversityAbstract Renal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor. We here tested its activity in RCC cells. In established and primary human RCC cells, PF-429242 potently inhibited cell proliferation, migration, and invasion. The S1P inhibitor provoked apoptosis activation in RCC cells. Furthermore, shRNA-mediated S1P silencing or CRISPR/Cas9-induced S1P knockout led to RCC cell growth inhibition and apoptosis activation. Conversely, ectopic overexpression of SREBP1 or S1P augmented RCC cell proliferation and migration. Daily i.v. injection of a single dose of PF-429242 robustly inhibited RCC xenograft growth in severe combined immunodeficiency mice. Additionally, intratumoral injection of S1P shRNA lentivirus inhibited RCC xenograft growth in mice. SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo.https://doi.org/10.1038/s41419-021-03999-9 |
| spellingShingle | Tong-bing Wang Mei Geng Hua Jin Ai-guo Tang Hao Sun Liu-zheng Zhou Bin-hai Chen Gang Shen Qiang Sun SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth Cell Death and Disease |
| title | SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth |
| title_full | SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth |
| title_fullStr | SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth |
| title_full_unstemmed | SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth |
| title_short | SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth |
| title_sort | srebp1 site 1 protease inhibitor pf 429242 suppresses renal cell carcinoma cell growth |
| url | https://doi.org/10.1038/s41419-021-03999-9 |
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