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, Byeol; Park, Yong Keun; Gil, Sung

doi:10.1038/sj.onc.1206478

Cited by 175 publications

(80 citation statements)

References 72 publications

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“…99 In fact, TGF-b itself has been reported to induce the phosphorylation of JAK1, STAT1, STAT3, and STAT5, 100 although this may be indirect, as TGF-b signaling induces IL-6 production, which can act in autocrine fashion to activate canonical JAK/STAT3 signaling. [101][102][103][104][105][106] Together, these studies support the cooperative intersection of activated-STAT3-and TGF-b-mediated signaling effectors. Yet, many other studies have reported disparate findings, suggesting that STAT3 activation and TGF-b signaling antagonize one another.…”

Section: Discussionsupporting

confidence: 48%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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Section: Discussionsupporting

confidence: 48%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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“…Besides a role in regulating apoptosis, active NF-kB is also able to stimulate proliferation through upregulation of genes that are involved in cell growth (Figure 7c). For example, recently it has been shown that the activated NF-kB pathway, in androgen-independent prostate cancer cells, is important for upregulation of interleukin-6 (IL-6) (Park et al, 2003;Zerbini et al, 2003). Since IL-6 has also been reported to stimulate growth of prostate cancer cells (Steiner et al, 2003), these cells will become more and more independent of growth factors and androgens.…”

Section: Discussionmentioning

confidence: 99%

Identification of REPS2 as a putative modulator of NF-κB activity in prostate cancer cells

2004

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The protein REPS2 is implicated in growth factor receptor-mediated endocytosis and signalling, and its expression is downregulated in androgen-independent prostate cancer cells. Herein, the NF-jB subunit p65 is identified as a human REPS2 protein partner, interacting with the EH domain of REPS2. Using crystal structure data from literature and experimental data from yeast and mammalian two-hybrid analysis, the results indicate that the NPF-motif in p65 acts as binding site for the EH domain in REPS2. However, in cultured prostate cancer cells, the REPS2-p65 interaction is triggered upon stimulation with phorbol ester (PMA). This indicates that PMA-sensitive signalling pathways can affect the interaction between REPS2 and p65. During prostate cancer progression from androgen-dependent to androgen-independent growth, downregulation of REPS2 is accompanied by upregulation of NF-jB activity. This might involve loss of REPS2-p65 interaction, which would lead to increased NF-jB activity. Androgen-deprivation causes apoptosis of prostate cancer cells, and activated NF-jB is a known inhibitor of apoptosis. Hence, decreased expression of REPS2 might be a key factor, causing prostate cancer cells to become resistant to induction of apoptosis by androgen deprivation.

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“…We have shown that SD-208 blocks TGF-␤1-triggered nuclear translocation of Smad2/3 and HIF-1␣, which regulate IL-6 and VEGF transcription, respectively (26,28). TGF-␤1 binds to a cell surface receptor complex consisting of T␤RI and T␤RII; T␤RII then activates T␤RI, which in turn phosphorylates Smad2/3.…”

Section: Discussionmentioning

confidence: 99%