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Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Oncogene volume 25, pages 4857–4866 (2006)Cite this article

Abstract

Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK–STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2–3.2 fold by 1 μ M paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 μ M in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 μ M), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.

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Acknowledgements

We thank Dr Chi-Neu Tsai (Chang Gung University) for helpful comments, Ching-Ling Wang and Shih-Yee Mimi Wang (University of Illinois) for technical assistance and Yinin Hu (Northwestern University) for editing help. This study was supported by CMRP890 and NSC92-2314-B-182A-054 (to TH Wang), CMRPG1012 (to TC Chang) and CMRP32049 and NSC92-2314-B-182-083 (to HS Wang).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

    T-H Wang, Y-H Chan, C-W Chen, T-C Chang & H-S Wang

  2. Genomic Medicine Research Core Laboratory (GMRCL), Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

    T-H Wang, W-H Kung & Y-S Lee

  3. Department of Biotechnology, Min Chuan University, Tao-Yuan, Taiwan

    Y-S Lee

  4. Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    S-T Wang

  5. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Gwei-Shan, Tao-Yuan, Taiwan

    H-S Wang

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  1. T-H Wang
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Correspondence to H-S Wang.

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Wang, TH., Chan, YH., Chen, CW. et al. Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways. Oncogene 25, 4857–4866 (2006). https://doi.org/10.1038/sj.onc.1209498

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