Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro.

Grandis, Jennifer R.; Drenning, Stephanie D.; Chakraborty, Arup; Zhou, Min; Zeng, Qing; Pitt, Allyson; Tweardy, David J.

doi:10.1172/jci3785

Cited by 449 publications

(387 citation statements)

References 43 publications

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“…EGFR has been shown to activate STAT3 in HNSCC. 35 This pathway appears to play an important role in resistance to apoptosis, 36 and recent evidence suggests it may contribute to VEGF expression in cardiac myocytes. 53 Finally, we have not excluded the possibility that EGFR and IL-1 could also modulate additional posttranscriptional and posttranslational mechanisms that affect cytokine secretion.…”

Section: Discussionmentioning

confidence: 99%

“…31 These signal components in turn have been shown to be able to activate several signal pathways that activate transcription factors, such as AP-1, 32 NF-B 33,34 and signal transduction and transcription factor-3 (STAT3). 35,36 In our study, we examined the effect of antagonists of EGFR, PI3K and MEK on NF-B and AP-1 activation and IL-8 and VEGF expression in HNSCC cell lines UM-SCC-9 and 11B. We provide evidence that EGFR can induce NF-B and AP-1 activation and IL-8 and VEGF expression in HNSCC and that antagonists of EGFR, PI3K and MEK have inhibitory activity against EGF-induced activation of these transcription and cytokine factors.…”

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confidence: 99%

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Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

218

190

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Key words: EGFR; NF-B; AP-1; IL-8; VEGF; PI3K; MEK; HNSCCIncreased angiogenesis is critical to tumor progression and metastasis, and we and others have shown that expression of members of the C-X-C cytokine and vascular endothelial growth factor families such as IL-8, growth regulated oncogene-1 (Gro 1) and VEGF can promote angiogenesis, tumorigenesis and metastatic tumor progression. 1-3 The expression of multiple factors with proangiogenic activity by cancer cells poses a significant obstacle to effective therapy with agents targeted toward individual factors and receptors. Identification of common mechanism(s) underlying expression of such a diversity of factors could guide the development of therapy using fewer selective agents. We previously observed that IL-8, VEGF and other cytokines are coexpressed and often vary concurrently in serum and supernatants from cell lines from different patients with head and neck squamous cell carcinoma (HNSCC), 4,5 suggesting that these factors could be regulated by common signal pathways or transcription factors.Examination of the regulatory region of many proinflammatory cytokines and proangiogenic factors reveals that they share common promoter sites for transcription factors such as nuclear factor-B (NF-B) and/or activator protein-1 (AP-1), which can be activated by injury, cytokines and growth factors. 6 We found that differences in expression of these cytokines in different cancers was often related to differences in constitutive activation of both NF-B and AP-1. 6 Inhibition of NF-B activation by expression of a dominant negative inhibitor-B or pharmacologic agents was found to inhibit expression of IL-8 and other proinflammatory and proangiogenic cytokines, 7-10 as well as tumorigenesis and angiogenesis in vivo. 7,9 Inhibition of activation of extracellular signalregulated kinase (ERK) and AP-1 with antagonists of mitogenactivated/extracellular signal-regulated kinase (MEK) partially inhibited expression of both IL-8 and VEGF. 10 These results provided evidence that at least 2 signal pathways upstream of NF-B and AP-1 make important contributions to expression of these angiogenesis factors.We have recently examined the contribution of several factors that may contribute to upstream signal activation of NF-B and AP-1 and expression of IL-8 and VEGF. We found that IL-1␣ expressed by HNSCC promotes autocrine activation of NF-B and AP-1, expression of IL-8 and cell survival. 11 Expression of IL-1 receptor antagonist inhibited NF-B reporter activity and IL-8 expression by 60 -80%, indicating that IL-1␣ is a major contributor to constitutive activation of NF-B and IL-8. HNSCC were also found to express c-MET, a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). 12 Increased expression of HGF/SF was detected together with IL-8 and VEGF in serum of patients with HNSCC, and recombinant HGF and HGF from stromal fibroblasts was found to further induce IL-8 and VEGF expression by human HNSCC lines. Inhibitors of MEK and Abbreviations: AP-1, activator...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

218

190

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“…Because of the critical role of Stat3 in head and neck carcinogenesis (Grandis et al, 1998(Grandis et al, , 2000 and our recent demonstration of sulindac-mediated downmodulation of Stat3 in oral SCCa (Nikitakis et al, 2002b), we explored the hypothesis that ligand-mediated PPARg activation causes changes in Stat3 expression and activation. Forty-five minutes of treatment with 20 mM of 15-PGJ 2 resulted in a significant reduction of phosphorylated Stat3 in SCC9 cells.…”

Section: Effects Of Ppar Agonists On Stat3 Phosphorylation and Expresmentioning

confidence: 99%

“…Here, we assessed the effects that the natural PPARg ligand 15-deoxy-D 12,14 -PGJ 2 (15-PGJ 2 ) and the synthetic PPARg ligands rosiglitazone and cigliatazone have on cell growth, apoptosis and cell proliferation in oral SCCa cells. Moreover, we explored the possibility that PPARg activation may affect the expression and activation of Stat3, an oncogene that plays a critical role in head and neck carcinogenesis (Grandis et al, 1998(Grandis et al, , 2000Bromberg et al, 1999;Bowman et al, 2000) and is downregulated by sulindac in oral SCCa cells (Nikitakis et al, 2002b).…”

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confidence: 99%

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

et al. 2002

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Activation of peroxisome proliferator-activated receptor gamma (PPARg) has been linked to induction of differentiation, cell growth inhibition and apoptosis in several types of human cancer. However, the possible effects of PPARg agonists on human oral squamous cell carcinoma have not yet been reported. In this study, treatment with 15-deoxy-D 12,14 -PGJ 2 (15-PGJ 2 ), a natural PPARg ligand, induced a significant reduction of oral squamous cell carcinoma cell growth, which was mainly attributed to upregulation of apoptosis. Interestingly, rosiglitazone and ciglitazone, two members of the thiazolidinedione family of PPARg activators, did not exert a growth inhibitory effect. Given the critical role that the oncogene signal transducer and activator of transcription 3 (Stat3) plays in head and neck carcinogenesis, its potential regulation by PPARg ligands was also examined. Treatment of oral squamous cell carcinoma cells with 15-PGJ 2 induced an initial reduction and eventual elimination of both phosphorylated and unphosphorylated Stat3 protein levels. In contrast, other PPARg did not induce similar effects. Our results provide the first evidence of significant antineoplastic effects of 15-PGJ 2 on human oral squamous cell carcinoma cells, which may be related to downmodulation of Stat3 and are at least partly mediated through PPARg-independent events.

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“…STAT3C, a construct constitutively activated by spontaneous dimmer formation, acquired the transforming activity scored by colony growth in soft agar and its tumor-forming potential in nude mice (Bromberg et al, 1999). Conversely, dominant-negative forms of STAT3 suppressed cell transformation with v-src oncogene (Bromberg et al, 1998) and the epidermal growth factor receptor (EGFR)-mediated autocrine growth of transformed epithelial cells (Grandis et al, 1998). These studies showed that activated STAT3 signaling directly involves in cell transformation.…”

Section: Introductionmentioning

confidence: 97%

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

et al. 2005

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Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine-and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP-1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.

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Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro.

Cited by 449 publications

References 43 publications

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

15-PGJ2, but not thiazolidinediones, inhibits cell growth, induces apoptosis, and causes downregulation of Stat3 in human oral SCCa cells

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

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