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Synergism of cytoplasmic kinases in IL6-induced ligand-independent activation of androgen receptor in prostate cancer cells

Oncogene volume 23, pages 1838–1844 (2004)Cite this article

Abstract

IL6 is a pleiotropic cytokine which has been implicated in ligand-independent activation of androgen receptor in prostate cancer cells. Here, we present the evidence that two cytoplasmic kinases Pim1 and Etk are involved in this process. We showed that Pim1 is expressed in all prostate cancer cell lines examined. Both the expression level and the kinase activity of Pim1 are regulated by IL6 in these cells. Furthermore, we showed that IL6 downstream tyrosine kinase Etk can induce tyrosine phosphorylation of Pim1 which is correlated with its kinase activity. Mutation of the conserved Tyrosine 218 in the activation loop results in reduced kinase activity of Pim1. Interestingly, Etk can also be activated by Pim1 when they are coexpressed in prostate cancer cells, suggesting a possible positive feedback loop between Etk and Pim1. It appears that both Pim1 and Etk are required for IL6-induced activation of androgen receptor-mediated transcription in prostate cancer cells because overexpression of the kinase-deficient form of either Pim1 or Etk dramatically blocks the IL6 effect. Coexpression of the two kinases together but neither one alone is sufficient to activate ARE-containing promoter. Taken together, our data suggest a synergism of Ser/Thr kinase Pim1 and tyrosine kinase Etk in IL6 signaling and provide new insights into ligand-independent activation of androgen receptor in prostate cancer cells.

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Acknowledgements

We thank Drs T Hirano and R Matusik for providing the constructs used in this study. This work was supported by NIH Grant (CA85380) and DOD Grant (PC020169) to YQ and DOD Postdoctoral Fellowship to ZG.

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Authors and Affiliations

  1. Department of Pharmacology & Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St, Baltimore, 21201, MD, USA

    Oekyung Kim, Tianyun Jiang, Yingqiu Xie, Zhiyong Guo & Yun Qiu

  2. Department of Epidemiology & Preventive Medicine, University of Maryland School of Medicine, Baltimore, 21201, MD, USA

    Hegang Chen

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  1. Oekyung Kim
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Correspondence to Yun Qiu.

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Kim, O., Jiang, T., Xie, Y. et al. Synergism of cytoplasmic kinases in IL6-induced ligand-independent activation of androgen receptor in prostate cancer cells. Oncogene 23, 1838–1844 (2004). https://doi.org/10.1038/sj.onc.1207304

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