Abstract:
:Ras, a small G-protein, physiologically directs cell proliferation and cell cycle via regulation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade. Dysregulation of Ras/MEK/ERK signaling has been reported to cause tumorigenesis and gliomas. Nobiletin, a citrus flavonoid, has been shown to have anti-tumor cells action. However, it remains elusive whether nobiletin could affect Ras activity. In this study, we provide the first evidence that nobiletin suppresses the proliferation by inhibiting Ras activity in C6 glioma cells, a rat glioma cell line. First, Ras pull-down assay showed that nobiletin inhibits Ras activity in a concentration-dependent manner in C6 cells. Second, farnesyltransferase inhibitor I, a Ras inhibitor, and U0126, a MEK inhibitor, induced an inhibition of the cell proliferation in C6 cells, while the cell proliferation was inhibited by nobiletin as well. Third, western blotting revealed that nobiletin showed inhibitory effects on MEK and ERK phopsphorylation levels in a concentration-dependent manner. Finally, such an inhibitory effect on the level of ERK phosphorylation by nobiletin was appreciably prevented by Gö6976, a selective inhibitor of conventional protein kinase Cs (PKCs) showing Ca(2+)-sensitivity, while GF109203X, a general inhibitor for PKCs, and BAPTA, a cell-permeable Ca(2+) chelator, to a lesser extent, suppressed a reduction of the phosphorylation. These findings suggest that the proliferation of C6 cells is Ras- and MEK/ERK signaling-dependent, and that nobiletin suppresses the cell proliferation by inhibiting Ras activity and MEK/ERK signaling cascade probably via a Ca(2+)-sensitive PKC-dependent mechanism. Thus, the natural compound has potential to be a therapeutic agent for glioma.
journal_name
Biol Pharm Bulljournal_title
Biological & pharmaceutical bulletinauthors
Aoki K,Yokosuka A,Mimaki Y,Fukunaga K,Yamakuni Tdoi
10.1248/bpb.b12-00824subject
Has Abstractpub_date
2013-01-01 00:00:00pages
540-7issue
4eissn
0918-6158issn
1347-5215pii
DN/JST.JSTAGE/bpb/b12-00824journal_volume
36pub_type
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