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TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer

Oncogene volume 28, pages 4353–4363 (2009)Cite this article

Abstract

Toll-like receptors (TLRs) expressed on immune cells trigger inflammatory responses. TLRs are also expressed on ovarian cancer (OvCa) cells, but the consequences of signaling by the TLR4/MyD88 pathway in these cells are unclear. Here, TLR4 and MyD88 expression in OvCa tissues (n=20) and cell lines (OVCAR3, SKOV3, AD10, A2780 and CP70) was evaluated by reverse transcriptase–PCR, western blots and immunohistochemistry. Cell growth, apoptosis, nuclear factor-κB (NF-κB) translocation, IRAK4 and TRIF expression and cJun phosphorylation were measured following tumor cell exposure to the TLR4 ligands, lipopolysaccharide (LPS) or paclitaxel (PTX). Culture supernatants were tested for cytokine levels. TLR4 was expressed in all tumors, tumor cell lines and normal epithelium. MyD88 was detectable in tumor tissues and in 3/5 OvCa lines but not in normal cells. In MyD88+ SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-κB pathway and promoted interleukin (IL)-8, IL-6, vascular endothelial growth factor and monocyte chemotactic protein-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with small interference RNA resulted in phosphorylated-cJun (p-cJun) downregulation and a loss of PTX resistance. In PTX-sensitive, MyD88neg A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect. Thus, TLR4/MyD88 signaling supports OvCa progression and chemoresistance, promoting immune escape.

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Acknowledgements

We thank B Hilldorfer for technical assistance and the Centre for Biologic Imaging at the University of Pittsburgh for assistance in performing confocal microscopy. This study was supported in part by NIH Grants PO1 CA109688 (TLW) and NO1-HB37165 (TLW) and by Heidi L Browning Ovarian Cancer Research Scholar Fund. Dr Szajnik was supported by the fellowship from the PACT Program of the National Heart Lung and Blood Institute (NHLBI).

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  1. M Szajnik and M J Szczepanski: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    M Szajnik, M J Szczepanski, M Czystowska, M Mandapathil & T L Whiteside

  2. Department of Gynecologic Oncology, Poznan University of Medical Sciences, Poznan, Poland

    M Szajnik & M Spaczynski

  3. Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland

    M J Szczepanski & E Nowak-Markwitz

  4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    E Elishaev & T L Whiteside

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Szajnik, M., Szczepanski, M., Czystowska, M. et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene 28, 4353–4363 (2009). https://doi.org/10.1038/onc.2009.289

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