title: Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice.
abstract: BACKGROUND
  Honokiol, a small-molecular weight natural product, has previously been reported to activate apoptosis and inhibit gastric tumorigenesis. Whether honokiol inhibits the angiogenesis and metastasis of gastric cancer cells remains unknown.
  
  
  RESULTS
  We tested the effects of honokiol on angiogenic activity and peritoneal dissemination using in vivo, ex vivo and in vitro assay systems. The signaling responses in human gastric cancer cells, human umbilical vascular endothelial cells (HUVECs), and isolated tumors were detected and analyzed. In a xenograft gastric tumor mouse model, honokiol significantly inhibited the peritoneal dissemination detected by PET/CT technique. Honokiol also effectively attenuated the angiogenesis detected by chick chorioallantoic membrane assay, mouse matrigel plug assay, rat aortic ring endothelial cell sprouting assay, and endothelial cell tube formation assay. Furthermore, honokiol effectively enhanced signal transducer and activator of transcription (STAT-3) dephosphorylation and inhibited STAT-3 DNA binding activity in human gastric cancer cells and HUVECs, which was correlated with the up-regulation of the activity and protein expression of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Calpain-II inhibitor and siRNA transfection significantly reversed the honokiol-induced SHP-1 activity. The decreased STAT-3 phosphorylation and increased SHP-1 expression were also shown in isolated peritoneal metastatic tumors. Honokiol was also capable of inhibiting VEGF generation, which could be reversed by SHP-1 siRNA transfection.
  
  
  CONCLUSIONS
  Honokiol increases expression and activity of SPH-1 that further deactivates STAT3 pathway. These findings also suggest that honokiol is a novel and potent inhibitor of angiogenesis and peritoneal dissemination of gastric cancer cells, providing support for the application potential of honokiol in gastric cancer therapy.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
authors.forename: Keh Bin
authors.initials: KB
authors.lastname: Wang
authors.forename: Keng Hsin
authors.initials: KH
authors.lastname: Lan
authors.forename: Wen Jane
authors.initials: WJ
authors.lastname: Lee
authors.forename: Hung Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Sheng Mao
authors.initials: SM
authors.lastname: Wu
authors.forename: Yen Chun
authors.initials: YC
authors.lastname: Peng
authors.forename: Yi Ching
authors.initials: YC
authors.lastname: Chen
authors.forename: Chin Chang
authors.initials: CC
authors.lastname: Shen
authors.forename: Hsu Chen
authors.initials: HC
authors.lastname: Cheng
authors.forename: Ko Kaung
authors.initials: KK
authors.lastname: Liao
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D002154:Calpain; D017705:Lignans; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols