PMID- 21882257
OWN - NLM
STAT- MEDLINE
DCOM- 20121130
LR  - 20181201
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Linking)
VI  - 51
IP  - 10
DP  - 2012 Oct
TI  - Silibinin modulates TNF-alpha and IFN-gamma mediated signaling to regulate COX2 and iNOS 
      expression in tumorigenic mouse lung epithelial LM2 cells.
PG  - 832-42
LID - 10.1002/mc.20851 [doi]
AB  - Silibinin inhibits mouse lung tumorigenesis in part by targeting tumor 
      microenvironment. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma 
      (IFN-gamma) can be pro- or anti-tumorigenic, but in lung cancer cell lines they 
      induce pro-inflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric 
      oxide synthase (iNOS). Accordingly, here we examined mechanism of silibinin 
      action on TNF-alpha + IFN-gamma (hereafter referred as cytokine mixture) elicited 
      signaling in tumor-derived mouse lung epithelial LM2 cells. Both signal 
      transducers and activators of the transcription (STAT)3 (tyr705 and ser727) and 
      STAT1 (tyr701) were activated within 15 min of cytokine mixture exposure, while 
      STAT1 (ser727) activated after 3 h. Cytokine mixture also activated Erk1/2 and 
      caused an increase in both COX2 and iNOS levels. Pretreatment of cells with a 
      MEK, NF-kappaB, and/or epidermal growth factor receptor (EGFR) inhibitor inhibited 
      cytokine mixture-induced activation of Erk1/2, NF-kappaB, or EGFR, respectively, and 
      strongly decreased phosphorylation of STAT3 and STAT1 and expression of COX2 and 
      iNOS. Also, janus family kinases (JAK)1 and JAK2 inhibitors specifically 
      decreased cytokine-induced iNOS expression, suggesting possible roles of JAK1, 
      JAK2, Erk1/2, NF-kappaB, and EGFR in cytokine mixture-caused induction of COX2 and 
      iNOS expression via STAT3/STAT1 activation in LM2 cells. Importantly, silibinin 
      pretreatment inhibited cytokine mixture-induced phosphorylation of STAT3, STAT1, 
      and Erk1/2, NF-kappaB-DNA binding, and expression of COX2, iNOS, matrix 
      metalloproteinases (MMP)2, and MMP9, which was mediated through impairment of 
      STAT3 and STAT1 nuclear localization. Silibinin also inhibited cytokine 
      mixture-induced migration of LM2 cells. Together, we showed that STAT3 and STAT1 
      could be valuable chemopreventive and therapeutic targets within the lung tumor 
      microenvironment in addition to being targets within tumor itself, and that 
      silibinin inhibits their activation as a plausible mechanism of its efficacy 
      against lung cancer.
CI  - Copyright (c) 2011 Wiley Periodicals, Inc.
FAU - Tyagi, Alpna
AU  - Tyagi A
AD  - Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado 
      Denver, Aurora, Colorado 80045, USA.
FAU - Agarwal, Chapla
AU  - Agarwal C
FAU - Dwyer-Nield, Lori D
AU  - Dwyer-Nield LD
FAU - Singh, Rana P
AU  - Singh RP
FAU - Malkinson, Alvin M
AU  - Malkinson AM
FAU - Agarwal, Rajesh
AU  - Agarwal R
LA  - eng
GR  - R01 CA113876/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110831
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (NF-kappa B)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Silymarin)
RN  - 0 (Stat1 protein, mouse)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 4RKY41TBTF (Silybin)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.99.- (Ptgs2 protein, mouse)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.24 (Mmp2 protein, mouse)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cyclooxygenase 2/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/drug effects/pathology
MH  - Interferon-gamma/*metabolism/pharmacology
MH  - Lung Neoplasms/*drug therapy/metabolism/pathology
MH  - MAP Kinase Kinase Kinases/antagonists & inhibitors
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - NF-kappa B/antagonists & inhibitors/metabolism
MH  - Nitric Oxide Synthase Type II/*metabolism
MH  - STAT1 Transcription Factor/metabolism
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction
MH  - Silybin
MH  - Silymarin/*pharmacology
MH  - Tumor Necrosis Factor-alpha/*metabolism/pharmacology
EDAT- 2011/09/02 06:00
MHDA- 2012/12/10 06:00
CRDT- 2011/09/02 06:00
PHST- 2011/06/30 00:00 [received]
PHST- 2011/08/01 00:00 [revised]
PHST- 2011/08/10 00:00 [accepted]
PHST- 2011/09/02 06:00 [entrez]
PHST- 2011/09/02 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - 10.1002/mc.20851 [doi]
PST - ppublish
SO  - Mol Carcinog. 2012 Oct;51(10):832-42. doi: 10.1002/mc.20851. Epub 2011 Aug 31.