Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer
Abstract Background As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridi...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-06-01
|
| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-020-07067-x |
| _version_ | 1818283302576979968 |
|---|---|
| author | Zhiyang Peng Qing Guan Jianfei Luo Wenhong Deng Jiasheng Liu Ruicheng Yan Weixing Wang |
| author_facet | Zhiyang Peng Qing Guan Jianfei Luo Wenhong Deng Jiasheng Liu Ruicheng Yan Weixing Wang |
| author_sort | Zhiyang Peng |
| collection | DOAJ |
| description | Abstract Background As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. Methods The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. Results Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted β-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3β-independent) or altered GSK3β activity, and thus exerted potent tumor-suppressive activities. Conclusion Sophoridine depends on targeting ESRRG/β-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer. |
| first_indexed | 2024-12-13T00:34:45Z |
| format | Article |
| id | doaj.art-9996a0151a39417fbdf2277da25808c9 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-13T00:34:45Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-9996a0151a39417fbdf2277da25808c92022-12-22T00:05:14ZengBMCBMC Cancer1471-24072020-06-0120111210.1186/s12885-020-07067-xSophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancerZhiyang Peng0Qing Guan1Jianfei Luo2Wenhong Deng3Jiasheng Liu4Ruicheng Yan5Weixing Wang6Department of Gastrointestinal Surgery in East Hospital, Renmin Hospital of Wuhan UniversityDepartment of Laboratory Medicine, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and ScienceDepartment of Gastrointestinal Surgery in East Hospital, Renmin Hospital of Wuhan UniversityDepartment of Gastrointestinal Surgery in East Hospital, Renmin Hospital of Wuhan UniversityDepartment of Gastrointestinal Surgery in East Hospital, Renmin Hospital of Wuhan UniversityDepartment of Gastrointestinal Surgery in East Hospital, Renmin Hospital of Wuhan UniversityDepartment of Gastrointestinal Surgery in East Hospital, Renmin Hospital of Wuhan UniversityAbstract Background As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. Methods The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. Results Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted β-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3β-independent) or altered GSK3β activity, and thus exerted potent tumor-suppressive activities. Conclusion Sophoridine depends on targeting ESRRG/β-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.http://link.springer.com/article/10.1186/s12885-020-07067-xGastric cancerSophoridineESRRGβ-Catenin |
| spellingShingle | Zhiyang Peng Qing Guan Jianfei Luo Wenhong Deng Jiasheng Liu Ruicheng Yan Weixing Wang Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer BMC Cancer Gastric cancer Sophoridine ESRRG β-Catenin |
| title | Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer |
| title_full | Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer |
| title_fullStr | Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer |
| title_full_unstemmed | Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer |
| title_short | Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer |
| title_sort | sophoridine exerts tumor suppressive activities via promoting esrrg mediated β catenin degradation in gastric cancer |
| topic | Gastric cancer Sophoridine ESRRG β-Catenin |
| url | http://link.springer.com/article/10.1186/s12885-020-07067-x |
| work_keys_str_mv | AT zhiyangpeng sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer AT qingguan sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer AT jianfeiluo sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer AT wenhongdeng sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer AT jiashengliu sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer AT ruichengyan sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer AT weixingwang sophoridineexertstumorsuppressiveactivitiesviapromotingesrrgmediatedbcatenindegradationingastriccancer |