Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression
Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC...
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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/1660-3397/16/6/212 |
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| author | Yu-Cheng Chen Mei-Chin Lu Mohamed El-Shazly Kuei-Hung Lai Tung-Ying Wu Yu-Ming Hsu Yi-Lun Lee Yi-Chang Liu |
| author_facet | Yu-Cheng Chen Mei-Chin Lu Mohamed El-Shazly Kuei-Hung Lai Tung-Ying Wu Yu-Ming Hsu Yi-Lun Lee Yi-Chang Liu |
| author_sort | Yu-Cheng Chen |
| collection | DOAJ |
| description | Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC), suppressed both the production of ROS from mitochondria and cell apoptosis that were induced by heteronemin treatment. Heteronemin upregulated talin and phosphorylated talin expression in Molt4 cells but it only upregulated the expression of phosphorylated talin in HEK293 cells. However, pretreatment with NAC reversed these effects. Talin siRNA reversed the activation of pro-apoptotic cleaved caspases 3 and 9. On the other hand, the downstream proteins including FAK and NF-κB (p65) were not affected. In addition, we confirmed that heteronemin directly modulated phosphorylated talin expression through ROS generation resulting in cell apoptosis, but it did not affect talin/FAK complex. Furthermore, heteronemin interfered with actin microfilament and caused morphology changes. Taken together, these findings suggest that the cytotoxic effect of heteronemin is associated with oxidative stress and induction of phosphorylated talin expression. Our results suggest that heteronemin represents an interesting candidate which can be further developed as a drug lead against leukemia. |
| first_indexed | 2024-04-13T09:20:10Z |
| format | Article |
| id | doaj.art-a7cf03353d9c4164853d64c23160ba52 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-13T09:20:10Z |
| publishDate | 2018-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-a7cf03353d9c4164853d64c23160ba522022-12-22T02:52:37ZengMDPI AGMarine Drugs1660-33972018-06-0116621210.3390/md16060212md16060212Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin ExpressionYu-Cheng Chen0Mei-Chin Lu1Mohamed El-Shazly2Kuei-Hung Lai3Tung-Ying Wu4Yu-Ming Hsu5Yi-Lun Lee6Yi-Chang Liu7The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, TaiwanGraduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, TaiwanDepartment of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 11566, EgyptNational Museum of Marine Biology & Aquarium, Pingtung 944, TaiwanGraduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanResearch Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Urology, Sinying Hospital, Ministry of Health and Welfare, Tainan 730, TaiwanDivision of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, TaiwanHeteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC), suppressed both the production of ROS from mitochondria and cell apoptosis that were induced by heteronemin treatment. Heteronemin upregulated talin and phosphorylated talin expression in Molt4 cells but it only upregulated the expression of phosphorylated talin in HEK293 cells. However, pretreatment with NAC reversed these effects. Talin siRNA reversed the activation of pro-apoptotic cleaved caspases 3 and 9. On the other hand, the downstream proteins including FAK and NF-κB (p65) were not affected. In addition, we confirmed that heteronemin directly modulated phosphorylated talin expression through ROS generation resulting in cell apoptosis, but it did not affect talin/FAK complex. Furthermore, heteronemin interfered with actin microfilament and caused morphology changes. Taken together, these findings suggest that the cytotoxic effect of heteronemin is associated with oxidative stress and induction of phosphorylated talin expression. Our results suggest that heteronemin represents an interesting candidate which can be further developed as a drug lead against leukemia.http://www.mdpi.com/1660-3397/16/6/212heteroneminreactive oxygen speciesmitochondrialtalinphosphorylated talin |
| spellingShingle | Yu-Cheng Chen Mei-Chin Lu Mohamed El-Shazly Kuei-Hung Lai Tung-Ying Wu Yu-Ming Hsu Yi-Lun Lee Yi-Chang Liu Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression Marine Drugs heteronemin reactive oxygen species mitochondrial talin phosphorylated talin |
| title | Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression |
| title_full | Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression |
| title_fullStr | Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression |
| title_full_unstemmed | Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression |
| title_short | Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression |
| title_sort | breaking down leukemia walls heteronemin a sesterterpene derivative induces apoptosis in leukemia molt4 cells through oxidative stress mitochondrial dysfunction and induction of talin expression |
| topic | heteronemin reactive oxygen species mitochondrial talin phosphorylated talin |
| url | http://www.mdpi.com/1660-3397/16/6/212 |
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