Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calmodulin-dependent protein kinases phosphorylate certain substrates that have been implicated in regulating cellular proliferation. For example, upon mitogenic stimulation, there is a rapid activation of calmodulin-dependent protein kinase III (CaM kinase III), which leads to the phosphorylation of elongation factor 2. Recently, our laboratory demonstrated that the activity of CaM kinase III is increased in glioma cells following exposure to mitogens and is diminished or absent in nonproliferating glial tissue. Rottlerin, a 5,7-dihydroxy-2,2-dimethyl-6-(2,4,6-trihydroxy-3-methyl-5-acetylbenzy l)-8-cinnamoyl-1,2-chromene isolated from the pericarps of Mallotus phillippinensis, has been shown to be an effective CaM kinase III inhibitor. Therefore, we evaluated the effects of rottlerin on the growth and viability of glioblastoma cell lines. Rottlerin decreased growth and induced cytotoxicity in rat (C6) and two human gliomas (T98G and U138MG) at concentrations that inhibited the activity of CaM kinase III in vitro and in vivo. Far less demonstrable effects were observed on other Ca2++/CaM-sensitive kinases. Incubation of glial cells with rottlerin produced a block at the G1-S interface and the appearance of a population of cells with a <2N complement of DNA. In addition, rottlerin induced changes in cellular morphology such as cell shrinkage, accumulation of cytoplasmic vacuoles, and packaging of cellular components within membranes. These data suggest that CaM kinase III may be an important link between the activation of CaM-dependent signaling, proliferation, and viability in malignant cells, and that inhibition of CaM kinase III may represent an interesting pharmacological target in malignant gliomas.
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PMID:Effects of rottlerin, an inhibitor of calmodulin-dependent protein kinase III, on cellular proliferation, viability, and cell cycle distribution in malignant glioma cells. 905 75

Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated. In the current study, we determine the function of rottlerin on glioma cell growth, apoptosis, cell cycle, migration and invasion. We found that rottlerin inhibited cell growth, migration, invasion, but induced apoptosis and cell cycle arrest. Mechanistically, the expression of Cdc20 oncoprotein was measured by the RT-PCR and Western blot analysis in glioma cells treated with rottlerin. We observed that rottlerin significantly inhibited the expression of Cdc20 in glioma cells, implying that Cdc20 could be a novel target of rottlerin. In line with this, over-expression of Cdc20 decreased rottlerin-induced cell growth inhibition and apoptosis, whereas down-regulation of Cdc20 by its shRNA promotes rottlerin-induced anti-tumor activity. Our findings indicted that rottlerin could exert its tumor suppressive function by inhibiting Cdc20 pathway which is constitutively active in glioma cells. Therefore, down-regulation of Cdc20 by rottlerin could be a promising therapeutic strategy for the treatment of glioma.
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PMID:Rottlerin inhibits cell growth and invasion via down-regulation of Cdc20 in glioma cells. 2762 99