Abstract
To explore the possible cross-talk between the IL-6 and TGF-beta1 pathways in AML blast cells, the effect of TGF-beta1 pretreatment on IL-6-induced STAT3 tyrosine phosphorylation was studied. A reduction of STAT3 tyrosine phosphorylation after TGF-beta1 pretreatment was observed in four out of 40 AML cases (10%), although all of the AML cases responded to TGF-beta1 by means of SMAD3 translocation. The reduced IL-6-mediated STAT3 tyrosine phosphorylation after pre-treatment with TGF-beta1 was associated with apoptosis and coincided with the degradation of certain cellular proteins, including JAK1 and -2 and Tyk2, without affecting the ERK expression and phosphorylation. Furthermore, treatment of AML blasts with the cytostatic agent VP16, as an alternative way to induce apoptosis, resulted in a similar degree of degradation of JAK kinases and concomitant reduction of IL-6-mediated STAT3 tyrosine phosphorylation. Although degradation of JAK kinases could be rescued by incubating the cells with the pan-caspase inhibitor Z-VAD-fmk, the attenuating effect of TGF-beta1 treatment on the STAT3 tyrosine phosphorylation was still partly present. It was shown that in AML cells cultured in the presence of Z-VAD-fmk, TGF-beta1 pretreatment resulted in a reduction of JAK1 phosphorylation upon IL-6 stimulation. Expression of SOCS1 and -3 could be ruled out as a possible cause of reduced JAK1 phosphorylation levels in the investigated AML case.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Annexin A5 / metabolism
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism*
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins / metabolism*
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Down-Regulation
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Electrophoretic Mobility Shift Assay
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Epithelial Cells / drug effects
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Etoposide / metabolism
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Etoposide / pharmacology
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Humans
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Interleukin-6 / pharmacology*
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 1
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology
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Phosphorylation
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Protein Transport
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Protein-Tyrosine Kinases / metabolism
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Repressor Proteins*
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Smad3 Protein
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tyrosine / metabolism
Substances
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Amino Acid Chloromethyl Ketones
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Annexin A5
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Antineoplastic Agents, Phytogenic
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Carrier Proteins
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Repressor Proteins
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SMAD3 protein, human
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SOCS1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Smad3 Protein
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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TGFB1 protein, human
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Trans-Activators
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Tyrosine
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Etoposide
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Janus Kinase 1
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CASP3 protein, human
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Caspase 3
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Caspases