Rhopaloic acid A induces apoptosis,autophagy and MAPK activation through ROS-mediated signaling in bladder cancer |
| |
| Affiliation: | 1. Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan;2. Division of Surgery, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan;3. Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Dapi Road, Niaosong District, Kaohsiung 83300, Taiwan;4. Department of Anatomy, School of Medicine, Department of Medical Research, Kaohsiung Medical University, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan;5. National Museum of Marine Biology and Aquarium, Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 94450, Taiwan;6. Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;7. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;8. Community Health Promotion Center, Kaohsiung Municipal Ci-Jin Hospital, Kaohsiung 80708, Taiwan;9. Department of Nutrition and Health Science, School of Medical and Health Sciences, Fooyin University, Kaohsiung 83102, Taiwan;10. Department of Pharmacology, School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Taiwan;11. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan;12. Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;1. Department of Stomatology, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, China;2. Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China;3. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, China;4. Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China;1. Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China;2. Department of Pharmacy, Shanghai Eye Diseases Prevention & Treatment Center, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai General Hospital, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200040, China |
| |
| Abstract: | BackgroundBladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown.PurposeThe present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism.MethodsCell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo.ResultsTreatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA. Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model.ConclusionTaken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
