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Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3

Oncogene volume 23, pages 4894–4902 (2004)Cite this article

An Erratum to this article was published on 16 December 2004

Abstract

Cell growth is promoted by mitogens and survival factors, which activate intracellular signalling pathways to control cell cycle progression and cellular integrity. Proliferation signals are transmitted through Ras and Rho family small G-proteins coupled to mitogen-activated protein kinase (MAPK) cascades, while survival signals are propagated by lipid-dependent kinases such as phosphatidylinositide 3-kinases (PI3Ks) and protein kinase B (Akt/PKB). Recently, signal transducer and activator of transcription (STAT) proteins were identified as positive regulators of proliferation in a variety of cell types. Persistent activation of these pathways is associated with tumour cell growth, whereas their inhibition can halt proliferation and precipitate apoptotic cell death. The human pathogen Pseudomonas aeruginosa uses quorum-sensing signal molecules (QSSMs) to regulate virulence gene expression. QSSMs also suppress host immune responses although the mechanism of suppression is unknown. Here, we demonstrate that the QSSM N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) from P. aeruginosa blocks proliferation and induces apoptosis in human BC cell lines. Analyses of signalling events reveal that OdDHL has little or no effect on MAPK cascades, partially inhibits the Akt/PKB pathway and ablates STAT3 activity. Pharmacological inhibition of each pathway independently indicates that STAT3 activity is critical for BC cell proliferation and survival, while a constitutively active STAT3 confers resistance to OdDHL. These results support the notion of OdDHL as a bioactive molecule in eukaryotic systems and a paradigm for a novel class of antiproliferative compounds.

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Acknowledgements

We thank Drs Cliff Murray, Charles Strueli and Sue Watson for the provision of cells, Drs Jim Darnell and Curt Horwath for the STAT3 expression vectors and Drs Adrian Robins, Lian Zhao and Julie Swales for assistance with the flow cytometry. We are also grateful to members of the group for discussions, to Drs Fred Sablitzsky and Jim Darnell for commenting on the manuscript and to Wendy Solis for secretarial assistance. This work was supported, in part, by grants from the AICR (to PES) and the MRC (to DP).

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Authors and Affiliations

  1. School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK

    Li Li & Peter E Shaw

  2. Immune Modulation Research Group, School of Pharmacy, University of Nottingham, NG7 2RD, UK

    Doreen Hooi, Siri Ram Chhabra & David Pritchard

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  1. Li Li
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  2. Doreen Hooi
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Correspondence to Peter E Shaw.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Li, L., Hooi, D., Chhabra, S. et al. Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3. Oncogene 23, 4894–4902 (2004). https://doi.org/10.1038/sj.onc.1207612

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