Abstract | BACKGROUND: METHODS: NEN cells were treated with ZM336372 (20 to 100 mumol/L) or carrier ( DMSO). Western Blot was used to determine the activation of the Raf-1/ MEK/ERK, other pathways activation, and cellular bioactive hormone production. RESULTS:
ZM336372 in NEN cells resulted in increasing raf-1 activation and inactivation of glycogen synthase kinase-3 beta (GSK-3beta) as measured by phosphorylation of ERK1/2 and GSK-3beta, respectively. There was no alteration in the levels of phosphorylated Akt, an important mediator of the phosphatidyl inositol 3 kinase pathway. Importantly, blocking of raf-1 pathway by U0126, a potent inhibitor, in the presence of ZM336372 did not reduce the levels of p-GSK-3beta, indicating that GSK-3beta inactivation is independent of raf-1 pathway activation. Moreover, the levels of chromogranin A and achaete-scute complex like-1 reductions were persistent even after blocking the raf-1 pathway. Treatment with ZM336372 in the presence of small interfering RNA against raf-1 resulted in an increase in Raf-1 production, suggesting that ZM336372 upregulates raf-1 at the transcriptional level. CONCLUSION: This is the first description of a novel compound ZM336372 that regulates multiple pathways in NEN cells.
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Authors | Muthusamy Kunnimalaiyaan, Mary Ndiaye, Herbert Chen |
Journal | Surgery
(Surgery)
Vol. 142
Issue 6
Pg. 959-64; discussion 959-64
(Dec 2007)
ISSN: 1532-7361 [Electronic] United States |
PMID | 18063082
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Benzamides
- N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide
- GSK3B protein, human
- Glycogen Synthase Kinase 3 beta
- Proto-Oncogene Proteins c-raf
- Extracellular Signal-Regulated MAP Kinases
- Glycogen Synthase Kinase 3
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Topics |
- Benzamides
(pharmacology)
- Carcinoid Tumor
- Carcinoma, Neuroendocrine
(drug therapy, metabolism, pathology)
- Cell Division
(drug effects)
- Cell Line, Tumor
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Glycogen Synthase Kinase 3
(metabolism)
- Glycogen Synthase Kinase 3 beta
- Humans
- Lung Neoplasms
- MAP Kinase Signaling System
(drug effects)
- Proto-Oncogene Proteins c-raf
(metabolism)
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