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.