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

Prostate. 2016 Dec;76(16):1469-1483. doi: 10.1002/pros.23230. Epub 2016 Jul 15.

Abstract

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.

Keywords: STAT3; c-MET; heteronemin; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents
  • Apoptosis / drug effects
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Humans
  • Male
  • Molecular Docking Simulation
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Serine Endopeptidases / drug effects
  • Signal Transduction / drug effects
  • Terpenes / chemistry
  • Terpenes / pharmacology*
  • c-Mer Tyrosine Kinase

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Terpenes
  • heteronemin
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase
  • HGF activator
  • Serine Endopeptidases
  • Caspase 8
  • Caspase 9