NF-κB-Induced IL-6 Ensures STAT3 Activation and Tumor Aggressiveness in Glioblastoma
Autor: | George B. Twitty, Etty N. Benveniste, G. Kenneth Gray, Rajani Rajbhandari, Suk W. Hong, Hao Yu, Susan Nozell, Braden C. McFarland |
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Rok vydání: | 2013 |
Předmět: |
STAT3 Transcription Factor
lcsh:Medicine Mice Nude Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Glioma medicine Animals Humans lcsh:Science STAT3 Transcription factor 030304 developmental biology Regulation of gene expression 0303 health sciences Multidisciplinary Interleukin-6 lcsh:R NF-kappa B NF-κB medicine.disease NFKB1 Neoplasm Proteins Gene Expression Regulation Neoplastic chemistry 030220 oncology & carcinogenesis Cancer research biology.protein Heterografts lcsh:Q Female Glioblastoma Neoplasm Transplantation Research Article |
Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 11, p e78728 (2013) |
ISSN: | 1932-6203 |
Popis: | Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly tumor of the central nervous system (CNS). In GBM, the transcription factors NF-κB and STAT3 are aberrantly activated and associated with tumor cell proliferation, survival, invasion and chemoresistance. In addition, common activators of NF-κB and STAT3, including TNF-α and IL-6, respectively, are abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling crosstalk that occurs between the NF-κB and STAT3 pathways in GBM tumors. Using cultured GBM cell lines as well as primary human GBM xenografts, we elucidated the signaling crosstalk between the NF-κB and STAT3 pathways utilizing approaches that either a) reduce NF-κB p65 expression, b) inhibit NF-κB activation, c) interfere with IL-6 signaling, or d) inhibit STAT3 activation. Using the clinically relevant human GBM xenograft model, we assessed the efficacy of inhibiting NF-κB and/or STAT3 alone or in combination in mice bearing intracranial xenograft tumors in vivo. We demonstrate that TNF-α-induced activation of NF-κB is sufficient to induce IL-6 expression, activate STAT3, and elevate STAT3 target gene expression in GBM cell lines and human GBM xenografts in vitro. Moreover, the combined inhibition of NF-κB and STAT3 signaling significantly increases survival of mice bearing intracranial tumors. We propose that in GBM, the activation of NF-κB ensures subsequent STAT3 activation through the expression of IL-6. These data verify that pharmacological interventions to effectively inhibit the activity of both NF-κB and STAT3 transcription factors must be used in order to reduce glioma size and aggressiveness. |
Databáze: | OpenAIRE |
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