Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways.
Interleukin-8 (IL-8) is known to contribute to human cancer progression through its potential function as a mitogenic, angiogenic, or motogenic factor. We found a high level of IL-8 production in SK-N-MC human primitive neuroectodermal tumor cells transfected with the human RET gene (SK-N-MC (RET) cells) in response to glial cell line-derived neurotrophic factor (GDNF) stimulation. IL-8 was also produced at high levels in TT human medullary thyroid carcinoma and TPC-1 human papillary thyroid carcinoma cell lines both of which express activated RET tyrosine kinase. To investigate which signaling pathways are responsible for IL-8 expression, we treated SK-N-MC (RET) cells with several kinase inhibitors before GDNF stimulation. The results showed that a MEK1 inhibitor, PD98059, a p38MAPK inhibitor, SB202190, and a protein kinase C (PKC) inhibitor, Calphostin C, markedly decreased the IL-8 secretion from SK-N-MC (RET) cells at 24 h after GDNF stimulation. In contrast, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, increased its secretion. These results thus suggested that IL-8 production by RET tyrosine kinase is regulated by multiple signaling pathways.
Iwahashi
Naoko
N
Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Murakami
Hideki
H
Nimura
Yuji
Y
Takahashi
Masahide
M
D029721:Drosophila Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
D029721:Drosophila Proteins; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D016209:Interleukin-8; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila