Document Detail


Modulation by staurosporine of phorbol-ester-induced effects on growth and protein kinase C localization in A549 human lung-carcinoma cells.
MedLine Citation:
PMID:  1563835     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
12-O-tetradecanoylphorbol-13-acetate (TPA) and bryostatin 1 are activators of protein kinase C (PKC). TPA is a potent inhibitor of the growth of A549 cells, while bryostatin 1 exerts a weak antiproliferative effect upon this cell line. We tested the hypothesis that the PKC inhibitor staurosporine (STAU) can interfere with the effects of TPA or bryostatin 1 on A549 cells. STAU alone arrested A549 cell growth effectively with an IC50 of 0.65 nM as determined by cell counting after incubation for 96 hr. It also caused the release of lactate dehydrogenase from cells with an IC50 of 18.4 nM. On incubation with cells for up to 8 hr, STAU (100 nM) alone did not reduce thymidine incorporation into cells. However, it partially abrogated the inhibition of DNA synthesis caused by TPA or bryostatin 1 (10 nM). The IC50 for inhibition by STAU of the activity of PKC purified from A549 cells was 6.1 nM. Localization and levels of PKC were studied by Western blot and phorbol ester receptor binding analyses. STAU (100 nM) did not prevent the TPA-induced rapid redistribution of PKC to the cell membrane, but instead increased it by 25%. The PKC downregulation caused by TPA was not reduced in the presence of STAU. The results suggest that (i) PKC activation is involved in growth inhibition caused by TPA or bryostatin 1 in A549 cells, and (ii) subcellular localization or levels of PKC can be pharmacologically manipulated even under conditions of inhibited kinase function.
Authors:
T D Bradshaw; A Gescher; G R Pettit
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  51     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  1992 Apr 
Date Detail:
Created Date:  1992-05-15     Completed Date:  1992-05-15     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  144-8     Citation Subset:  IM    
Affiliation:
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
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MeSH Terms
Descriptor/Qualifier:
Alkaloids / pharmacology*
Bryostatins
Cell Division / drug effects
DNA / biosynthesis*
Down-Regulation
Enzyme Activation / drug effects
Humans
Lactones / pharmacology
Lung Neoplasms / enzymology*,  pathology*
Macrolides
Protein Kinase C / antagonists & inhibitors,  metabolism*
Staurosporine
Tetradecanoylphorbol Acetate / pharmacology
Grant Support
ID/Acronym/Agency:
CA 16049-12/CA/NCI NIH HHS; CA-44344-01A1/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Alkaloids; 0/Bryostatins; 0/Lactones; 0/Macrolides; 16561-29-8/Tetradecanoylphorbol Acetate; 62996-74-1/Staurosporine; 83314-01-6/bryostatin 1; 9007-49-2/DNA; EC 2.7.11.13/Protein Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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