期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 43, 期 5, 页码 784-794出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2011.02.002
关键词
PKC-iota; Cdk7; Neuroblastoma; Proliferation; Apoptosis
资金
- Research Service of the James A. Haley Veteran's Hospital
- Inhibiton Therapeutics Inc.
- Evan T.J. Dunbar Neuroblastoma Foundation
- William and Ella Owens Medical Research Foundation
- Margaret Ewell Dickens Foundation
Protein Kinase C-iota (PKC-iota), 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-iota 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-iota inhibitor in neuroblastoma cell proliferation and apoptosis. ICA-1 specifically inhibits the activity of PKC-iota but not that of PKC-zeta (PKC-zeta), the closely related atypical PKC family member. The IC50 for the kinase activity assay was approximately 0.1 mu M which is 1000 times less than that of aurothiomalate, a known PKC-iota inhibitor. Cyclin dependent kinase 7 (Cdk7) phosphorylates cyclin dependent kinases (cdks) and promotes cell proliferation. Our data shows that PKC-iota is an in vitro Cdk7 kinase and the phosphorylation of Cdk7 by PKC-iota was potently inhibited by ICA-1. Furthermore, our data shows that neuroblastoma cells proliferate via a PKC-iota/Cdk7/cdk2 cell signaling pathway and ICA-1 mediates its antiproliferative effects by inhibiting this pathway. ICA-1 (0.1 mu M) 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-iota inhibitor and chemotherapeutic agent for neuroblastoma. Published by Elsevier Ltd.
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