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Small molecule 1′-acetoxychavicol acetate suppresses breast tumor metastasis by regulating the SHP-1/STAT3/MMPs signaling pathway

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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.

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Acknowledgments

This work was supported by Grants from the Chenguang Program of Shanghai Municipal Education Commission (10CG25 to X. Pang), the National Natural Science Foundation of China (81101683 to X. Pang), the National Basic Research Program of China (2012CB910401 to M. Liu), and the Fundamental Research Funds for the Central Universities (78260029 to X. Pang).

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None declared.

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Authors and Affiliations

  1. 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

    Jieqiong Wang, Li Zhang, Guoliang Chen, Jing Zhang, Zhenxi Li, Weiqiang Lu, Mingyao Liu & Xiufeng Pang

  2. Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, 77030, USA

    Mingyao Liu

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  1. Jieqiong Wang
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  2. Li Zhang
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Correspondence to Xiufeng Pang.

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Jieqiong Wang and Li Zhang have contributed equally to this work.

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Wang, J., Zhang, L., Chen, G. et al. Small molecule 1′-acetoxychavicol acetate suppresses breast tumor metastasis by regulating the SHP-1/STAT3/MMPs signaling pathway. Breast Cancer Res Treat 148, 279–289 (2014). https://doi.org/10.1007/s10549-014-3165-6

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  • DOI: https://doi.org/10.1007/s10549-014-3165-6

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