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

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

Research output: Contribution to journalArticlepeer-review

160 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4314-4332
Number of pages19
JournalOncogene
Volume22
Issue number28
DOIs
Publication statusPublished - 2003 Jul 10

Keywords

  • C-Jun
  • IL-6
  • Nuclear factor-κB
  • Prostate cancer
  • Smad
  • TGF-β1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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