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.
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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 © 2016 Wiley Periodicals, Inc.
The Prostate. 2016 Jul 15 [Epub ahead of print]
Jian-Ching Wu, Chiang-Ting Wang, Han-Chun Hung, Wen-Jeng Wu, Deng-Chyang Wu, Min-Chi Chang, Ping-Jyun Sung, Yu-Wei Chou, Zhi-Hong Wen, Ming-Hong Tai
Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan., Department of Urological Surgery, Kaohsiung Armed Force General Hospital, Kaohsiung, Taiwan., Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan., Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan., Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan., Division of Colorectal Surgery, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan., National Museum of Marine Biology and Aquarium, Pingtung, Taiwan., Tissue Bank and BioBank, Kaohsiung Chang Gung Memorial Hospital, Niao-Song District, Kaohsiung, Taiwan., Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan., Doctoral Degree Program in Marine Biotechnology, Academia Sinica, National Sun Yat-sen University, Kaohsiung, Taiwan.