Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-06-20

AUTHORS

Qing Xu, Jon Briggs, Sungman Park, Guilian Niu, Marcin Kortylewski, Shumin Zhang, Tanya Gritsko, James Turkson, Heidi Kay, Gregg L Semenza, Jin Q Cheng, Richard Jove, Hua Yu

ABSTRACT

Vascular endothelial growth factor (VEGF) upregulation is induced by many receptor and intracellular oncogenic proteins commonly activated in cancer, rendering molecular targeting of VEGF expression a complex challenge. While VEGF inducers abound, only two major transcription activators have been identified for its promoter: hypoxia inducible factor-1 (HIF-1) and signal transducer and activator of transcription (Stat3). Both HIF-1 expression and Stat3 activity are upregulated in diverse cancers. Here, we provide evidence that Stat3 is required for both basal and growth signal-induced expression of HIF-1. Moreover, induction of VEGF by diverse oncogenic growth stimuli, including IL-6R, c-Src, Her2/Neu, is attenuated in cells without Stat3 signaling. We further demonstrate that Stat3 regulates expression of Akt, which is required for growth signal-induced HIF-1 upregulation. Targeting Stat3 with a small-molecule inhibitor blocks HIF-1 and VEGF expression in vitro and inhibits tumor growth and angiogenesis in vivo. Furthermore, tumor cells' in vivo angiogenic capacity induced by IL-6R, which simultaneously activates Jak/STAT and PI3K/Akt pathways, is abrogated when Stat3 is inhibited. Activation of Stat3 signaling by various growth signaling is prevalent in diverse cancers. Results presented here demonstrate that Stat3 is an effective target for inhibiting tumor VEGF expression and angiogenesis. More... »

PAGES

5552-5560

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  • Journal

    TITLE

    Oncogene

    ISSUE

    36

    VOLUME

    24

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/sj.onc.1208719

    DOI

    http://dx.doi.org/10.1038/sj.onc.1208719

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1044728544

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/16007214


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