NF-κB-Induced IL-6 Ensures STAT3 Activation and Tumor Aggressiveness in Glioblastoma

• Published in: PloS one Vol. 8; no. 11; p. e78728
• Main Authors: McFarland, Braden C., Hong, Suk W., Rajbhandari, Rajani, Twitty, George B., Gray, G. Kenneth, Yu, Hao, Benveniste, Etty N., Nozell, Susan E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.11.2013; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Biology; Biotechnology; Brain cancer; Brain tumors; Cell Line, Tumor; Cell proliferation; Cell survival; Central nervous system; Chemoresistance; Crosstalk; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genomics; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - therapy; Glioma; Heterografts; Humans; Immunoglobulins; Interleukin 6; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Kinases; Mice; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Transplantation; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Pathways; Pharmacology; Proteins; Signal transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stem cells; Survival; Transcription factors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; Xenografts; Xenotransplantation; Alabama; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078728

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.