Details

Autor(en) / Beteiligte

• Wu, Jian-Ching
• Wang, Chiang-Ting
• Hung, Han-Chun
• Wu, Wen-Jeng
• Wu, Deng-Chyang
• Chang, Min-Chi
• Sung, Ping-Jyun
• Chou, Yu-Wei
• Wen, Zhi-Hong
• Tai, Ming-Hong

Titel

Heteronemin Is a Novel c-Met/STAT3 Inhibitor Against Advanced Prostate Cancer Cells

Ist Teil von

• The Prostate, 2016-12, Vol.76 (16), p.1469-1483

Ort / Verlag

United States: Blackwell Publishing Ltd

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Wiley HSS Collection

Beschreibungen/Notizen

• BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.