Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells.
The Jak/Stat signaling pathway transmits signals from many cytokine and growth factor receptors to target genes in the nucleus. Constitutive activation of Stat3 has recently been observed in many tumor cells and dysregulation of the Stat signaling pathway has been proposed to be implicated in malignant transformation. In a previous study, we found constitutively tyrosine phosphorylated Stat3 in mycosis fungoides tumor cells. Here, we show that the Jak kinase inhibitor, Ag490, inhibits the constitutive binding of Stat3 to an oligonucleotide representing the Stat-binding sequence from the ICAM promotor. The decreased ability of Stat3 to bind DNA precedes dynamic alterations in the expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins (decreased Bcl-2 expression and increased Bax expression) and induction of apoptosis. Thus, our data suggest that the involvement of Stat3 in oncogenic transformation could be mediated through regulation of survival signals.
Nielsen
M
M
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
Kaestel
C G
CG
Eriksen
K W
KW
Woetmann
A
A
Stokkedal
T
T
Kaltoft
K
K
Geisler
C
C
Röpke
C
C
Odum
N
N
D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009182:Mycosis Fungoides / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D011817:Rabbits; D050796:STAT3 Transcription Factor; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051028:bcl-2-Associated X Protein; D011505:Protein-Tyrosine Kinases