1. Calpain/SHP-1 Interaction by Honokiol Dampening Peritoneal Dissemination of Gastric Cancer in nu/nu Mice
- Author
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Yi-Ching Chen, Wen Jane Lee, Sheng Mao Wu, Ko Kaung Liao, Keng Hsin Lan, Yen Chun Peng, Meei-Ling Sheu, Keh Bin Wang, Hsu-Chen Cheng, Shing-Hwa Liu, Hung Chuan Pan, and Chin Chang Shen
- Subjects
Honokiol ,Mouse ,Angiogenesis ,Cancer Treatment ,lcsh:Medicine ,Apoptosis ,Metastasis ,chemistry.chemical_compound ,Mice ,Basic Cancer Research ,Phosphorylation ,RNA, Small Interfering ,lcsh:Science ,Cells, Cultured ,Stomach and Duodenum ,Tube formation ,Multidisciplinary ,Neovascularization, Pathologic ,Chemistry ,Calpain ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,Transfection ,Animal Models ,Chicken ,Up-Regulation ,Endothelial stem cell ,Oncology ,Medicine ,Antiangiogenesis Therapy ,Research Article ,Signal Transduction ,STAT3 Transcription Factor ,Gastroenterology and Hepatology ,Lignans ,Model Organisms ,Stomach Neoplasms ,Cell Line, Tumor ,Gastrointestinal Tumors ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Biology ,Cell Proliferation ,lcsh:R ,Biphenyl Compounds ,Cancers and Neoplasms ,medicine.disease ,Molecular biology ,Xenograft Model Antitumor Assays ,Gastric Cancer ,Cancer cell ,Cancer research ,Rat ,lcsh:Q ,Ex vivo - 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.
- Published
- 2012