PMID- 24244348
OWN - NLM
STAT- MEDLINE
DCOM- 20140722
LR  - 20220316
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 11
DP  - 2013
TI  - NF-kappaB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in 
      glioblastoma.
PG  - e78728
LID - 10.1371/journal.pone.0078728 [doi]
LID - e78728
AB  - Glioblastoma (GBM) is the most aggressive, neurologically destructive and deadly 
      tumor of the central nervous system (CNS). In GBM, the transcription factors 
      NF-kappaB and STAT3 are aberrantly activated and associated with tumor cell 
      proliferation, survival, invasion and chemoresistance. In addition, common 
      activators of NF-kappaB and STAT3, including TNF-alpha and IL-6, respectively, are 
      abundantly expressed in GBM tumors. Herein, we sought to elucidate the signaling 
      crosstalk that occurs between the NF-kappaB 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-kappaB and STAT3 pathways utilizing approaches 
      that either a) reduce NF-kappaB p65 expression, b) inhibit NF-kappaB 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-kappaB and/or STAT3 alone or in combination in mice bearing 
      intracranial xenograft tumors in vivo. We demonstrate that TNF-alpha-induced 
      activation of NF-kappaB 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-kappaB and STAT3 signaling 
      significantly increases survival of mice bearing intracranial tumors. We propose 
      that in GBM, the activation of NF-kappaB ensures subsequent STAT3 activation through 
      the expression of IL-6. These data verify that pharmacological interventions to 
      effectively inhibit the activity of both NF-kappaB and STAT3 transcription factors 
      must be used in order to reduce glioma size and aggressiveness.
FAU - McFarland, Braden C
AU  - McFarland BC
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      at Birmingham, Birmingham, Alabama, United States of America.
FAU - Hong, Suk W
AU  - Hong SW
FAU - Rajbhandari, Rajani
AU  - Rajbhandari R
FAU - Twitty, George B Jr
AU  - Twitty GB Jr
FAU - Gray, G Kenneth
AU  - Gray GK
FAU - Yu, Hao
AU  - Yu H
FAU - Benveniste, Etty N
AU  - Benveniste EN
FAU - Nozell, Susan E
AU  - Nozell SE
LA  - eng
GR  - T32 NS048039/NS/NINDS NIH HHS/United States
GR  - R01 CA158534/CA/NCI NIH HHS/United States
GR  - P50 CA097247/CA/NCI NIH HHS/United States
GR  - T32NS048039/NS/NINDS NIH HHS/United States
GR  - R01CA138517/CA/NCI NIH HHS/United States
GR  - R01 CA138517/CA/NCI NIH HHS/United States
GR  - R01CA158534/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131111
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (NF-kappa B)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Glioblastoma/genetics/*metabolism/pathology/therapy
MH  - Heterografts
MH  - Humans
MH  - Interleukin-6/*biosynthesis/genetics
MH  - Mice
MH  - Mice, Nude
MH  - NF-kappa B/genetics/*metabolism
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - Neoplasm Transplantation
MH  - STAT3 Transcription Factor/genetics/*metabolism
PMC - PMC3823708
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/11/19 06:00
MHDA- 2014/07/23 06:00
PMCR- 2013/11/11
CRDT- 2013/11/19 06:00
PHST- 2013/06/25 00:00 [received]
PHST- 2013/09/16 00:00 [accepted]
PHST- 2013/11/19 06:00 [entrez]
PHST- 2013/11/19 06:00 [pubmed]
PHST- 2014/07/23 06:00 [medline]
PHST- 2013/11/11 00:00 [pmc-release]
AID - PONE-D-13-26196 [pii]
AID - 10.1371/journal.pone.0078728 [doi]
PST - epublish
SO  - PLoS One. 2013 Nov 11;8(11):e78728. doi: 10.1371/journal.pone.0078728. 
      eCollection 2013.