Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway
Abstract Background Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-022-00537-x |
| _version_ | 1818064858421133312 |
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| author | Bingwu Wang Jian Gao Zhongjun Zhao Xuefei Zhong Hao Cui Hui Hou Yanping Zhang Junnian Zheng Jiehui Di Yong Liu |
| author_facet | Bingwu Wang Jian Gao Zhongjun Zhao Xuefei Zhong Hao Cui Hui Hou Yanping Zhang Junnian Zheng Jiehui Di Yong Liu |
| author_sort | Bingwu Wang |
| collection | DOAJ |
| description | Abstract Background Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics. Methods Based on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening. Results One of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferation in vitro and in vivo. Mechanistic study reveals that MDM2 is required for S9-induced G2 cell cycle arrest and apoptosis, whereas p53 contributes to S9-induced apoptosis. Conclusions Putting together, S9 may serve as a lead compound for the development of an anticancer drug that specifically targets RPL11-MDM2-p53 pathway. |
| first_indexed | 2024-12-10T14:42:41Z |
| format | Article |
| id | doaj.art-78a722e51e2c48dfa07b2e4f25246dcc |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-10T14:42:41Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-78a722e51e2c48dfa07b2e4f25246dcc2022-12-22T01:44:39ZengBMCMolecular Medicine1076-15511528-36582022-09-0128111510.1186/s10020-022-00537-xIdentification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathwayBingwu Wang0Jian Gao1Zhongjun Zhao2Xuefei Zhong3Hao Cui4Hui Hou5Yanping Zhang6Junnian Zheng7Jiehui Di8Yong Liu9Cancer Institute, Xuzhou Medical UniversityJiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityDepartment of Radiation and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel HillCenter of Clinical Oncology, Affiliated Hospital of Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityAbstract Background Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics. Methods Based on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening. Results One of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferation in vitro and in vivo. Mechanistic study reveals that MDM2 is required for S9-induced G2 cell cycle arrest and apoptosis, whereas p53 contributes to S9-induced apoptosis. Conclusions Putting together, S9 may serve as a lead compound for the development of an anticancer drug that specifically targets RPL11-MDM2-p53 pathway.https://doi.org/10.1186/s10020-022-00537-xS9RPL11-MDM2-p53 pathwayCell proliferationCell cycle arrestApoptosis |
| spellingShingle | Bingwu Wang Jian Gao Zhongjun Zhao Xuefei Zhong Hao Cui Hui Hou Yanping Zhang Junnian Zheng Jiehui Di Yong Liu Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway Molecular Medicine S9 RPL11-MDM2-p53 pathway Cell proliferation Cell cycle arrest Apoptosis |
| title | Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway |
| title_full | Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway |
| title_fullStr | Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway |
| title_full_unstemmed | Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway |
| title_short | Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway |
| title_sort | identification of a small molecule rpl11 mimetic that inhibits tumor growth by targeting mdm2 p53 pathway |
| topic | S9 RPL11-MDM2-p53 pathway Cell proliferation Cell cycle arrest Apoptosis |
| url | https://doi.org/10.1186/s10020-022-00537-x |
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