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 journalArticle

151 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
Externally publishedYes

Fingerprint

MAP Kinase Signaling System
Transforming Growth Factors
Interleukin-6
Prostatic Neoplasms
Transcription Factor AP-1
Prostate
Transfection
Carcinogenesis
Neoplasms
Growth Inhibitors
Curcumin

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

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

In: Oncogene, Vol. 22, No. 28, 10.07.2003, p. 4314-4332.

Research output: Contribution to journalArticle

Park, Jae Il ; Lee, Min Goo ; Cho, Kyucheol ; Park, Bum Joon ; Chae, Kwon Seok ; Byun, Do Sun ; Ryu, Byung Kyu ; Park, Yong Keun ; Chi, Sung-Gil. / 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. In: Oncogene. 2003 ; Vol. 22, No. 28. pp. 4314-4332.
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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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T1 - 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

AU - Park, Jae Il

AU - Lee, Min Goo

AU - Cho, Kyucheol

AU - Park, Bum Joon

AU - Chae, Kwon Seok

AU - Byun, Do Sun

AU - Ryu, Byung Kyu

AU - Park, Yong Keun

AU - Chi, Sung-Gil

PY - 2003/7/10

Y1 - 2003/7/10

N2 - 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.

AB - 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.

KW - C-Jun

KW - IL-6

KW - Nuclear factor-κB

KW - Prostate cancer

KW - Smad

KW - TGF-β1

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