Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice
Journal
PLoS ONE
Journal Volume
7
Journal Issue
8
Date Issued
2012
Author(s)
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. Methodology/Principal Findings: 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/Significance: 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. ? 2012 Liu et al.
SDGs
Other Subjects
calpain 2; fluorodeoxyglucose f 18; honokiol; protein tyrosine phosphatase SHP 1; small interfering RNA; STAT3 protein; vasculotropin; animal experiment; animal model; animal tissue; antiangiogenic activity; article; computer assisted emission tomography; controlled study; enzyme activity; ex vivo study; human; human cell; in vitro study; in vivo study; metastasis inhibition; mouse; nonhuman; peritoneum metastasis; protein dephosphorylation; protein DNA binding; protein expression; protein phosphorylation; protein protein interaction; signal transduction; stomach cancer; upregulation; Animals; Apoptosis; Biphenyl Compounds; Calpain; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Mice; Neovascularization, Pathologic; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Up-Regulation; Xenograft Model Antitumor Assays
Type
journal article