title: Heteronemin Is a Novel c-Met/STAT3 Inhibitor Against Advanced Prostate Cancer Cells.
abstract: Prostate cancer is one of the most prevalent cancers in men worldwide. Aberrant activation of c-Met/signal transducer and activator of transcription-3 (STAT3) signaling is involved in prostate carcinogenesis, underscoring the demand for developing c-Met/STAT3-targeting drugs. Thus, we first utilized virtual screening strategy to identify STAT3-inhibiting marine compound, heteronemin, and then validated the STAT3-inhibiting function of heteronemin in prostate cancer cells.
  
  
  
  Human prostate cancer LNCaP, DU145, and PC-3 cell lines were treated with heteronemin for 24 hr, then the cell viability was evaluated by MTT assay. Flow cytometry was performed to analyze the apoptosis in heteronemin-treated cells. Western blot and quantitative real-time PCR were executed to further confirm the c-Met/STAT3 signaling inhibition by heteronemin in DU145 and PC-3 cells.
  
  
  
  In this study, we employed the virtual screening strategy to identify heteronemin, a spongean sesterterpene, as a potential STAT3 inhibitor from Taiwan marine drugs library. Application of heteronemin potently suppressed the viability and anchorage-independent growth of human prostate cancer cells. Besides, heteronemin induced apoptosis in prostate cancer cells by activation of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways. By luciferase assay and expression analysis, it was confirmed that heteronemin inhibited the phosphorylation of c-Met/src/STAT3 signaling axis, STAT3-driven luciferase activities and expression of STAT3-regulated genes including Bcl-xL, Bcl-2, and Cyclin D1. Finally, heteronemin effectively antagonized the hepatocyte growth factor (HGF)-stimulated c-Met/STAT3 activation as well as the proliferation and colonies formation in refractory prostate cancer cells.
  
  
  
  These findings suggest that heteronemin may constitute a novel c-Met/STAT3-targeting agent for prostate cancer. Prostate 76:1469-1483, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Jian-Ching
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Department of Urological Surgery, Kaohsiung Armed Force General Hospital, Kaohsiung, Taiwan.|Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Wang
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Han-Chun
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Jeng
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Faculty of Medicine, Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Division of Colorectal Surgery, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Min-Chi
authors.initials: MC
authors.lastname: Chang
authors.affiliation: National Museum of Marine Biology and Aquarium, Pingtung, Taiwan.|Institute of Marine Biotechnology, National Dong Hwa University, Pingtung, Taiwan.
authors.forename: Ping-Jyun
authors.initials: PJ
authors.lastname: Sung
authors.affiliation: Tissue Bank and BioBank, Kaohsiung Chang Gung Memorial Hospital, Niao-Song District, Kaohsiung, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chou
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan. wzh@mail.nsysu.edu.tw.|Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan. wzh@mail.nsysu.edu.tw.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Wen
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan. minghongtai@gmail.com.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan. minghongtai@gmail.com.|Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung, Taiwan. minghongtai@gmail.com.|Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan. minghongtai@gmail.com.
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Tai
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D013729:Terpenes; C493748:heteronemin; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; C081092:HGF activator; D012697:Serine Endopeptidases; D053181:Caspase 8; D053453:Caspase 9
keywords: STAT3; c-MET; heteronemin; prostate cancer