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Transforming growth factor-β1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways

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Abstract

Transforming growth factor (TGF)-β1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-β1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-β1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-β1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-β1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-κB (NF-κB), JNK, and Ras. TGF-β1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by TGF-β1 was accompanied by nuclear translocation of NF-κB, which was blocked by the p38 inhibitors SB202190 and SB203580 or by IκBαΔN transfection, indicating the crucial role for the p38-NF-κB signaling in TGF-β1 induction of IL-6. TGF-β1 activated c-Jun phosphorylation, and IL-6 induction by TGF-β1 was severely impeded by DN-c-Jun and DN-JNK or AP-1 inhibitor curcumin, showing that the JNK-c-Jun-AP-1 signaling plays a pivotal role in TGF-β1 stimulation of IL-6. It was also found that the Ras-Raf-MEK1 cascade is activated by TGF-β1 and participates in the TGF-β1 induction of IL-6 in an AP-1-dependent manner. Cotransfection assays demonstrated that TGF-β1 stimulation of IL-6 results from the synergistic collaboration of the Smad2, p38-NF-κB, JNK-c-Jun-AP-1, or Ras-Raf-MEK1 cascades. In addition, a time course IL-6 decay revealed that mRNA stability of IL-6 is modestly increased by TGF-β1, indicating that TGF-β1 also regulates IL-6 at the post-transcriptional level. Intriguingly, IL-6 inactivation restored the sensitivity to TGF-β1-mediated growth arrest and apoptosis, suggesting that elevated IL-6 in advanced prostate tumors might act as a resistance factor against TGF-β1. Collectively, our data demonstrate that IL-6 expression is stimulated by tumor-producing TGF-β1 in human prostate cancer cells through multiple signaling pathways including Smad2, p38, JNK, and Ras, and enhanced expression of IL-6 could contribute to the oncogenic switch of TGF-β1 role for prostate tumorigenesis, in part by counteracting its growth suppression function.

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Acknowledgements

This research was supported in part by a grant from Korea Research Foundation (Basic Medical Research Fund, 1998), a grant from the Basic Research Program of the Korea Science and Engineering Foundation (R02-2002-00035-0), and Intramural Grant-in-Aid from the Kyung Hee University (2000), Seoul, Korea.

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  1. Jae-Il Park and Min-Goo Lee: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathology, College of Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Jae-Il Park, Min-Goo Lee, Kyucheol Cho, Bum-Joon Park, Kwon-Seok Chae, Do-Sun Byun, Byung-Kyu Ryu & Sung-Gil Chi

  2. Graduate School of Life Science and Biotechnology, Korea University, Seoul, 136-701, Republic of Korea

    Yong-Keun Park

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  1. Jae-Il Park
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Park, JI., Lee, MG., Cho, K. et al. Transforming growth factor-β1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways. Oncogene 22, 4314–4332 (2003). https://doi.org/10.1038/sj.onc.1206478

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