heteronemin and Prostatic-Neoplasms

Topics: Animals; Apoptosis; Autophagy; Benzoquinones; Cell Line, Tumor; DNA Topoisomerases, Type II; Endoplasmic Reticulum Stress; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Lactams, Macrocyclic; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Mitochondria; Molecular Docking Simulation; Oxidative Stress; Prostate; Prostatic Neoplasms; Protein Binding; Terpenes; Topoisomerase II Inhibitors; Xenograft Model Antitumor Assays

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.

Topics: Antineoplastic Agents; Apoptosis; c-Mer Tyrosine Kinase; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enzyme Activation; Humans; Male; Molecular Docking Simulation; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins; Real-Time Polymerase Chain Reaction; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Signal Transduction; STAT3 Transcription Factor; Terpenes