Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells.
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.
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.
Kenichi
K
Wakabayashi
Fukushi
F
Kambe
Xia
X
Cao
Ryuichiro
R
Murakami
Hirohito
H
Mitsuyama
Takashi
T
Nagaya
Kiyoshi
K
Saito
Jun
J
Yoshida
Hisao
H
Seo
D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase; D016209:Interleukin-8 / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D000001:Calcimycin; D016572:Cyclosporine; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium