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Inhibitory effects of cyclosporin A on calcium
mobilization-dependent interleukin-8 expression and invasive potential of human
glioblastoma U251MG cells
Kenichi Wakabayashi, Fukushi Kambe, Xia Cao, Ryuichiro Murakami,
Hirohito Mitsuyama, Takashi Nagaya, Kiyoshi Saito, Jun Yoshida and
Hisao Seo
Department of Endocrinology and Metabolism, Division of Molecular
and Cellular Adaptation, Research Institute of Environmental Medicine,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan [K.W.,
F.K., X.C., R.M., H.M., T.N., H.S.]. Department of Neurosurgery,
School of Medicine, Nagoya University, Nagoya 466-8550, Japan [K.W.,
K.S., J.Y.]. Correspondence to: F Kambe, E-mail:
kambe@riem.nagoya-u.ac.jp.
Interleukin (IL)-8 produced from glioblastoma is suggested to contribute to its
own proliferation and progression.
Since various external stimuli have been
shown to increase intracellular Ca(2+) in glioma cells, we investigated Ca(2+)
mobilization-dependent IL-8 expression and effect of cyclosporin A (CsA), an
inhibitor of calcineurin (Cn), on the expression and invasive potential of human
glioblastoma U251MG cells.
Combined treatment with Ca(2+)-ionophore and
phorbol-myristate-acetate (A23187/PMA) increased IL-8 mRNA and protein levels.
This increase was suppressed by CsA and by another Cn inhibitor FK506.
Luciferase reporter gene assay and electrophoretic mobility shift assay revealed
that activation of p65-containing nuclear factor-kappaB was essential for
A23187/PMA-dependent activation of IL-8 promoter.
CsA suppressed the promoter
activity by attenuating IkappaB-alpha degradation.
U251MG cells expressed IL-8
receptors CXCR-1 and -2, and Matrigel invasion assay revealed that CsA
attenuated A23187/PMA-dependent stimulation of invasive potential, probably by
inhibiting IL-8 production.
In addition, IL-8-dependent proliferation was also
suppressed by CsA.
Taken together, these results demonstrate the novel
inhibitory effects of CsA on glioblastoma cell functions, suggesting CsA as a
potential therapeutic adjuvant for glioma treatment.
Source: http://www.nature.com/cgi-taf/DynaPage.taf?file=/onc/journal/v23/n41/abs/1207778a.html
DOI: http://dx.doi.org/10.1038/sj.onc.1207778
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