title: Small molecule 1'-acetoxychavicol acetate suppresses breast tumor metastasis by regulating the SHP-1/STAT3/MMPs signaling pathway.
abstract: Signal transducer and activator of transcription 3 (STAT3) is implicated breast cancer metastasis and represents a potential target for developing new anti-tumor metastasis drugs. The purpose of this study is to investigate whether the natural agent 1'-acetoxychavicol acetate (ACA), derived from the rhizomes and seeds of Languas galanga, could suppress breast cancer metastasis by targeting STAT3 signaling pathway. ACA was examined for its effects on breast cancer migration/invasion and metastasis using Transwell assays in vitro and breast cancer skeletal metastasis mouse model in vivo (n = 10 mice per group). The inhibitory effect of ACA on cellular STAT3 signaling pathway was investigated by series of biochemistry analysis. The chavicol preferentially suppressed cancer cell migration and invasion, and this activity was superior to its cytotoxic effects. ACA suppressed both constitutive and interleukin-6-inducible STAT3 activation and diminished the accumulation of STAT3 in the nucleus and its DNA-binding activity. More importantly, ACA treatment led to significant up-regulation of Src homology region 2 domain-containing phosphatase 1 (SHP-1), and the ACA-induced depression of cancer cell migration and STAT3 signaling could be apparently reversed by blockade of SHP-1. Matrix metalloproteinase (MMP)-2 and -9, gene products of STAT3 that regulate cell invasion, were specifically suppressed by ACA. In tumor metastasis model, ACA potently inhibited the human breast cancer cell-induced osteolysis, and had little apparent in vivo toxicity at the test concentrations. ACA is a novel drug candidate for the inhibition of tumor metastasis through interference with the SHP-1/STAT3/MMPs signaling pathway.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Guoliang
authors.initials: G
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Li
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001592:Benzyl Alcohols / Q000627:therapeutic use*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000627:therapeutic use; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D001592:Benzyl Alcohols; D010936:Plant Extracts; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; C047948:1'-acetoxychavicol acetate