A novel PKC-ι inhibitor abrogates cell proliferation and induces apoptosis in neuroblastoma.
Protein Kinase C-iota (PKC-ι), an atypical protein kinase C isoform manifests its potential as an oncogene by targeting various aspects of cancer cells such as growth, invasion and survival. PKC-ι confers resistance to drug-induced apoptosis in cancer cells. The acquisition of drug resistance is a major obstacle to good prognosis ... in neuroblastoma. The focus of this research was to identify the efficacy of [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) as a novel PKC-ι inhibitor in neuroblastoma cell proliferation and apoptosis. ICA-1 specifically inhibits the activity of PKC-ι but not that of PKC-zeta (PKC-ζ), the closely related atypical PKC family member. The IC(50) for the kinase activity assay was approximately 0.1μM which is 1000 times less than that of aurothiomalate, a known PKC-ι inhibitor. Cyclin dependent kinase 7 (Cdk7) phosphorylates cyclin dependent kinases (cdks) and promotes cell proliferation. Our data shows that PKC-ι is an in vitro Cdk7 kinase and the phosphorylation of Cdk7 by PKC-ι was potently inhibited by ICA-1. Furthermore, our data shows that neuroblastoma cells proliferate via a PKC-ι/Cdk7/cdk2 cell signaling pathway and ICA-1 mediates its antiproliferative effects by inhibiting this pathway. ICA-1 (0.1μM) inhibited the in vitro proliferation of BE(2)-C neuroblastoma cells by 58% (P=0.01). Additionally, ICA-1 also induced apoptosis in neuroblastoma cells. Interestingly, ICA-1 did not affect the proliferation of normal neuronal cells suggesting its potential as chemotherapeutic with low toxicity. Hence, our results emphasize the potential of ICA-1 as a novel PKC-ι inhibitor and chemotherapeutic agent for neuroblastoma.
Mesh Terms:
Apoptosis, Binding, Competitive, Caspase 3, Catalytic Domain, Cell Line, Tumor, Cell Proliferation, Cell Survival, Chromatin Assembly and Disassembly, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, DNA Fragmentation, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Imidazoles, Inhibitory Concentration 50, Isoenzymes, Models, Molecular, Neuroblastoma, Phosphoric Acid Esters, Phosphorylation, Poly(ADP-ribose) Polymerases, Protein Kinase C, Protein Kinase Inhibitors, Signal Transduction
Apoptosis, Binding, Competitive, Caspase 3, Catalytic Domain, Cell Line, Tumor, Cell Proliferation, Cell Survival, Chromatin Assembly and Disassembly, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinases, DNA Fragmentation, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Imidazoles, Inhibitory Concentration 50, Isoenzymes, Models, Molecular, Neuroblastoma, Phosphoric Acid Esters, Phosphorylation, Poly(ADP-ribose) Polymerases, Protein Kinase C, Protein Kinase Inhibitors, Signal Transduction
Int. J. Biochem. Cell Biol.
Date: May. 01, 2011
PubMed ID: 21315177
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