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The Fer tyrosine kinase cooperates with interleukin-6 to activate signal transducer and activator of transcription 3 and promote human prostate cancer cell growth

McGill University Health Center Research Institute, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4.
Molecular Cancer Research (Impact Factor: 4.5). 02/2009; 7(1):142-55. DOI: 10.1158/1541-7786.MCR-08-0117
Source: PubMed

ABSTRACT Androgen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgen-independent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6-mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate cancer.

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    • "There are also reports that suggest a supportive role of FER in the proliferation and growth of malignant cells [20] [21]. Actually, several reports have suggested its roles in cancers [22], including prostate cancer [20] [23], colon cancer [24], breast cancer [21], hepatocellular carcinoma [25], malignant mesothelioma [26], or gastric cancer [27]; however, to the best of our knowledge, the present study is the first report to correlate FER with lung cancer. "
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    • "We also found that the amount of the laminin-binding to p120-catenin (Piedra et al., 2003), and Fer down-regulation resulted in a decrease in E-cadherin protein (Supplemental Figure S4). Previously Fer was shown to activate STAT3 and promote human prostate cancer cell growth (Zoubeidi et al., 2009). Thus we asked whether STAT3 interacts with Fer in breast cancer cell lines. "
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