Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis

Niu, Guilian; Wright, Kenneth L.; Huang, Mei; Song, Lanxi; Haura, Eric B.; Turkson, James; Zhang, Shumin; Wang, Tianhong; Sinibaldi, Dominic; Coppola, Domenico; Heller, Richard; Ellis, Lee M.; Karras, James G.; Bromberg, Jacqueline; Pardoll, Drew M.; Jove, Richard; Yu, Hua

doi:10.1038/sj.onc.1205260

Cited by 1,055 publications

(911 citation statements)

References 43 publications

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“…We further examined whether silencing of IL-6 or its downstream target STAT3 in vector or ILK-overexpressing cells could affect VEGF expression. We found a significant decrease in VEGF protein in ILK-overexpressing cells knocked down for IL-6 or its downstream target STAT3, suggessting that ILK may activate STAT3 through enhanced IL-6 production and thereby induces VEGF expression, as activated STAT3 is known to bind to VEGF promoter (Niu et al, 2002).…”

Section: Discussionmentioning

confidence: 72%

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

et al. 2011

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Integrin-linked kinase (ILK) is a highly conserved serinethreonine protein kinase involved in cell-extracellular matrix interactions, cytoskeletal organization and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. However, the molecular mechanism by which ILK enhances melanoma progression is currently unknown. In the present study, we found that proangiogenic molecule interleukin-6 (IL-6) is the downstream target of ILK in melanoma cells. ILK overexpression increased IL-6, whereas silencing of ILK suppressed IL-6 expression at both messenger RNA and protein levels. ILK also altered the activity and subcellular localization of nuclear factor-kappaB (NF-jB) subunit p65. We further found that ILK enhanced the IL-6 gene transcription by promoting the binding of NF-kB p65 to IL-6 promoter. Moreover, ILK overexpression in melanoma cells enhanced the tube-forming ability of endothelial cells in vitro and microvessel formation in vivo. ILK-induced tube and blood vessel formation of endothelial cells was significantly reduced upon IL-6 inhibition in ILK-overexpressing melanoma cells. To delineate the mechanism by which ILK-induced IL-6 production can enhance angiogenesis, further analysis of the downstream targets of IL-6 signaling showed an increased activity of the signal transducer and activator of transcription 3 (STAT3) in ILK-overexpressing cells. As STAT3 binds to vascular endothelial growth factor (VEGF) promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined upon transfection of IL-6 small interfering RNA, suggesting that ILK may regulate VEGF expression through IL-6 pathway by activating STAT3.

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Section: Discussionmentioning

confidence: 72%

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

et al. 2011

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“…For example, STAT3 plays an important role in oncogenesis by upregulating the transcription of several genes that control tumor cell survival, resistance to apoptosis, cell cycle progression and angiogenesis. Target genes of STAT3 include Bcl-2 (Bhattacharya et al, 2005), Bcl-X L (Bromberg et al, 1999), c-myc (Kiuchi et al, 1999) and Mcl-1 (Epling-Burnette et al, 2001), and genes encoding cyclin D1 (Bromberg et al, 1999), vascular endothelial growth factor (Niu et al, 2002) and human telomerase reverse transcriptase (Konnikova et al, 2005). It was previously shown in many cancer cell types that when the STAT3 pathway was blocked by AG490, the expression of the STAT3 target genes was downregulated and apoptosis was induced (Meydan et al, 1996;EplingBurnette et al, 2001;Rahaman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

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“…These results are in line with those of Wei et al 27 and others showing that constitutive STAT3 activity upregulates VEGF expression and tumor angiogenesis. 48,49 A putative upstream STAT binding element at nt À842 to À849 in the VEGF promoter was recently ascribed to be involved in STAT3-mediated VEGF expression. 48 However, in our progressive deletion analysis, IL-6 is still increasing VEGF transcription even in the absence of this upstream promoter region, indicating that IL-6-induced VEGF transcription is not dependent on the supposed STAT binding element at nt À842 to À849 in the VEGF promoter.…”

Section: Discussionmentioning

confidence: 99%

“…48,49 A putative upstream STAT binding element at nt À842 to À849 in the VEGF promoter was recently ascribed to be involved in STAT3-mediated VEGF expression. 48 However, in our progressive deletion analysis, IL-6 is still increasing VEGF transcription even in the absence of this upstream promoter region, indicating that IL-6-induced VEGF transcription is not dependent on the supposed STAT binding element at nt À842 to À849 in the VEGF promoter. Because both dominant-negative STAT3 and constitutively active STAT3 are capable of regulating IL-6-triggered VEGF transcription through the SBE-less À88/À50 VEGF promoter, we hypothesize that IL-6 drives VEGF expression via STAT3 and Sp1 in a novel noncanonical way.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

Loeffler

Fayard

Weis

et al. 2005

Intl Journal of Cancer

191

134

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Interleukin-6 (IL-6) expression is strongly correlated with the degree of human glioma malignancy and necessary for tumor formation in a mouse model of spontaneous astrocytomas. Yet, exactly how IL-6 contributes to malignant progression of these brain tumors is still unclear. We have scrutinized the mechanism of transcriptional activation of vascular endothelial growth factor (VEGF) expression by IL-6 in the mouse brain and in glioblastoma cells. We demonstrate here that IL-6 drives transcriptional upregulation of VEGF in astrocytes in vivo using glial fibrillary acidic protein (GFAP)-IL-6/VEGF-green fluorescent protein (GFP) double transgenic mice. We further show that IL-6-induced VEGF transcription and VEGF secretion by human glioblastoma cells is dependent on signal transducer and activator of transcription 3 (STAT3). By progressive 5 0 -deletion analysis we defined the minimal VEGF promoter region for IL-6-responsiveness to nucleotides 288/250. Surprisingly, this promoter region is rich in GC-boxes and does not contain STAT3 binding elements. Electrophoretic mobility shift and supershift assays revealed binding of Sp1 and Sp3 to the 288/250 element upon IL-6 stimulation. Interestingly, preincubation with STAT3 antibody prevented the binding of Sp1 and Sp3 to the 288/250 element, indicating that STAT3 is involved in IL-6-driven Sp1/Sp3 protein-DNA complex formation. Physical interaction of STAT3 and Sp1 was demonstrated by coimmunoprecipitation. The functional relevance of the STAT3/ Sp1 association was corroborated by transient transfection experiments, which showed that overexpression of constitutively active STAT3 increased the minimal VEGF promoter activity. Taken together, our study suggests that IL-6 promotes tumor angiogenesis in gliomas and describes a novel transcriptional activation mechanism for STAT3 in the context of a STAT3 binding element (SBE)-free promoter. ' 2005 Wiley-Liss, Inc.

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Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis

Cited by 1,055 publications

References 43 publications

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

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