Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3
Abstract Background The development of potent non-toxic chemotherapeutic drugs against castration resistant prostate cancer (CRPC) remains a major challenge. Corosolic acid (CA), a natural triterpenoid, has anti-cancer activity with limited side effects. However, CA anti-prostate cancer activities a...
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| Format: | Article |
| Language: | English |
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BMC
2018-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0889-x |
| _version_ | 1818433636232331264 |
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| author | Bo Ma Hang Zhang Yu Wang Ang Zhao Zhiming Zhu Xiaowen Bao Yang Sun Lin Li Qi Zhang |
| author_facet | Bo Ma Hang Zhang Yu Wang Ang Zhao Zhiming Zhu Xiaowen Bao Yang Sun Lin Li Qi Zhang |
| author_sort | Bo Ma |
| collection | DOAJ |
| description | Abstract Background The development of potent non-toxic chemotherapeutic drugs against castration resistant prostate cancer (CRPC) remains a major challenge. Corosolic acid (CA), a natural triterpenoid, has anti-cancer activity with limited side effects. However, CA anti-prostate cancer activities and mechanisms, particularly in CRPC, are not clearly understood. In this study, we investigated CA anti-tumor ability against human CRPC and its mechanism of action. Methods The cell apoptosis and proliferation effects were evaluated via MTT detection, colony formation assay and flow cytometry. Western blot, gene transfection and immunofluorescence assay were applied to investigate related protein expression of Endoplasmic reticulum stress. A xenograft tumor model was established to investigate the inhibitory effect of CA on castration resistant prostate cancer in vivo. Results The results showed that CA inhibited cell growth and induced apoptosis in human prostate cancer cell (PCa) line PC-3 and DU145, as well as retarded tumor growth in a xenograft model, exerting a limited toxicity to normal cells and tissues. Importantly, CA activated endoplasmic reticulum (ER) stress-associated two pro-apoptotic signaling pathways, as evidenced by increased protein levels of typical ER stress markers including IRE-1/ASK1/JNK and PERK/eIF2α/ATF4/CHOP. IRE-1, PERK or CHOP knockdown partially attenuated CA cytotoxicity against PCa cells. Meanwhile, CHOP induced expression increased Tribbles 3 (TRIB3) level, which lead to AKT inactivation and PCa cell death. CHOP silencing resulted in PCa cells sensitive to CA-induced apoptosis. Conclusion Our data demonstrated, for the first time, that CA might represent a novel drug candidate for the development of an anti-CRPC therapy. |
| first_indexed | 2024-12-14T16:24:14Z |
| format | Article |
| id | doaj.art-f49dfcb104294ab0a0c192e805b7ebba |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-14T16:24:14Z |
| publishDate | 2018-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-f49dfcb104294ab0a0c192e805b7ebba2022-12-21T22:54:45ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-09-0137111610.1186/s13046-018-0889-xCorosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3Bo Ma0Hang Zhang1Yu Wang2Ang Zhao3Zhiming Zhu4Xiaowen Bao5Yang Sun6Lin Li7Qi Zhang8School of Pharmaceutical Sciences, Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversityInstitute of Advanced Materials (IAM), Nanjing Tech UniversitySchool of Pharmaceutical Sciences, Nanjing Tech UniversityAbstract Background The development of potent non-toxic chemotherapeutic drugs against castration resistant prostate cancer (CRPC) remains a major challenge. Corosolic acid (CA), a natural triterpenoid, has anti-cancer activity with limited side effects. However, CA anti-prostate cancer activities and mechanisms, particularly in CRPC, are not clearly understood. In this study, we investigated CA anti-tumor ability against human CRPC and its mechanism of action. Methods The cell apoptosis and proliferation effects were evaluated via MTT detection, colony formation assay and flow cytometry. Western blot, gene transfection and immunofluorescence assay were applied to investigate related protein expression of Endoplasmic reticulum stress. A xenograft tumor model was established to investigate the inhibitory effect of CA on castration resistant prostate cancer in vivo. Results The results showed that CA inhibited cell growth and induced apoptosis in human prostate cancer cell (PCa) line PC-3 and DU145, as well as retarded tumor growth in a xenograft model, exerting a limited toxicity to normal cells and tissues. Importantly, CA activated endoplasmic reticulum (ER) stress-associated two pro-apoptotic signaling pathways, as evidenced by increased protein levels of typical ER stress markers including IRE-1/ASK1/JNK and PERK/eIF2α/ATF4/CHOP. IRE-1, PERK or CHOP knockdown partially attenuated CA cytotoxicity against PCa cells. Meanwhile, CHOP induced expression increased Tribbles 3 (TRIB3) level, which lead to AKT inactivation and PCa cell death. CHOP silencing resulted in PCa cells sensitive to CA-induced apoptosis. Conclusion Our data demonstrated, for the first time, that CA might represent a novel drug candidate for the development of an anti-CRPC therapy.http://link.springer.com/article/10.1186/s13046-018-0889-xCorosolic acid (CA)Endoplasmic reticulum stress (ER stress)CCAAT-enhancer-binding protein homologous protein (CHOP)Tribbles homolog 3 (TRIB3)Castration resistant PCa (CRPC)Protein kinase RNA-like endoplasmic reticulum kinase (PERK) |
| spellingShingle | Bo Ma Hang Zhang Yu Wang Ang Zhao Zhiming Zhu Xiaowen Bao Yang Sun Lin Li Qi Zhang Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 Journal of Experimental & Clinical Cancer Research Corosolic acid (CA) Endoplasmic reticulum stress (ER stress) CCAAT-enhancer-binding protein homologous protein (CHOP) Tribbles homolog 3 (TRIB3) Castration resistant PCa (CRPC) Protein kinase RNA-like endoplasmic reticulum kinase (PERK) |
| title | Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 |
| title_full | Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 |
| title_fullStr | Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 |
| title_full_unstemmed | Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 |
| title_short | Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 |
| title_sort | corosolic acid a natural triterpenoid induces er stress dependent apoptosis in human castration resistant prostate cancer cells via activation of ire 1 jnk perk chop and trib3 |
| topic | Corosolic acid (CA) Endoplasmic reticulum stress (ER stress) CCAAT-enhancer-binding protein homologous protein (CHOP) Tribbles homolog 3 (TRIB3) Castration resistant PCa (CRPC) Protein kinase RNA-like endoplasmic reticulum kinase (PERK) |
| url | http://link.springer.com/article/10.1186/s13046-018-0889-x |
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