Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90
Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further expl...
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| Format: | Article |
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MDPI AG
2018-06-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/16/6/204 |
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| author | Man-Gang Lee Yi-Chang Liu Yi-Lun Lee Mohamed El-Shazly Kuei-Hung Lai Shou-Ping Shih Seng-Chung Ke Ming-Chang Hong Ying-Chi Du Juan-Cheng Yang Ping-Jyun Sung Zhi-Hong Wen Mei-Chin Lu |
| author_facet | Man-Gang Lee Yi-Chang Liu Yi-Lun Lee Mohamed El-Shazly Kuei-Hung Lai Shou-Ping Shih Seng-Chung Ke Ming-Chang Hong Ying-Chi Du Juan-Cheng Yang Ping-Jyun Sung Zhi-Hong Wen Mei-Chin Lu |
| author_sort | Man-Gang Lee |
| collection | DOAJ |
| description | Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent. |
| first_indexed | 2024-04-11T13:21:10Z |
| format | Article |
| id | doaj.art-351f43ec22bc4b0886839ccdaa3e99a3 |
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| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T13:21:10Z |
| publishDate | 2018-06-01 |
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| series | Marine Drugs |
| spelling | doaj.art-351f43ec22bc4b0886839ccdaa3e99a32022-12-22T04:22:11ZengMDPI AGMarine Drugs1660-33972018-06-0116620410.3390/md16060204md16060204Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90Man-Gang Lee0Yi-Chang Liu1Yi-Lun Lee2Mohamed El-Shazly3Kuei-Hung Lai4Shou-Ping Shih5Seng-Chung Ke6Ming-Chang Hong7Ying-Chi Du8Juan-Cheng Yang9Ping-Jyun Sung10Zhi-Hong Wen11Mei-Chin Lu12Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, TaiwanDivision of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, TaiwanDepartment of Urology, Sinying Hospital, Ministry of Health and Welfare, Tainan 730, TaiwanDepartment of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 115, EgyptGraduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, TaiwanDoctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, 70 Lien-Hai Road, Kaohsiung 804, TaiwanDivision of Urology, Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, TaiwanDepartment and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, TaiwanGraduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, TaiwanResearch Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, TaiwanDepartment of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, TaiwanGraduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, TaiwanHeteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.http://www.mdpi.com/1660-3397/16/6/204antitumorapoptosisautophagyER stressheteroneminHsp90topoisomerase II catalytic inhibitor |
| spellingShingle | Man-Gang Lee Yi-Chang Liu Yi-Lun Lee Mohamed El-Shazly Kuei-Hung Lai Shou-Ping Shih Seng-Chung Ke Ming-Chang Hong Ying-Chi Du Juan-Cheng Yang Ping-Jyun Sung Zhi-Hong Wen Mei-Chin Lu Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 Marine Drugs antitumor apoptosis autophagy ER stress heteronemin Hsp90 topoisomerase II catalytic inhibitor |
| title | Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 |
| title_full | Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 |
| title_fullStr | Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 |
| title_full_unstemmed | Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 |
| title_short | Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90 |
| title_sort | heteronemin a marine sesterterpenoid type metabolite induces apoptosis in prostate lncap cells via oxidative and er stress combined with the inhibition of topoisomerase ii and hsp90 |
| topic | antitumor apoptosis autophagy ER stress heteronemin Hsp90 topoisomerase II catalytic inhibitor |
| url | http://www.mdpi.com/1660-3397/16/6/204 |
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