A role for protein kinase C delta in the differential sensitivity of MCF-7 and MDA-MB 231 human breast cancer cells to phorbol ester-induced growth arrest and p21(WAFI/CIP1) induction.
The goal of this study was to investigate the differential sensitivity of estrogen receptor (ER) positive MCF-7 and ER negative MDA-MB 231 breast cancer cells to phorbol myristate acetate (PMA)-dependent growth arrest. MCF-7 cells were growth arrested by 80% while MDA-MB 231 cells were arrested by 20% in response to seven days of treatment with 10 nM PMA. Coincident with the increased sensitivity of MCF-7 cells to be growth arrested by the protein kinase C (PKC) activator PMA, PMA induced 9-fold higher levels of the cyclin dependent kinase (Cdk) inhibitor p21(WAF1/GIP1) in MCF-7 compared to MDA-MB 231 cells. A comparison of the PKC isoforms expressed in MCF-7 versus MDA-MB 231 cells showed that only the PMA-sensitive PKC delta and eta isoforms were expressed at markedly (> or =10-fold) elevated levels in MCF7 versus MDA-MB 231 cells. These results suggested that the differential sensitivity to growth arrest and induction of p2l(WAFl/CIPl) could reflect, at least in part, increased expression of PMA-dependent PKC isoforms delta and/or eta. Direct evidence to support this hypothesis was provided by the ability of transient transfections into MCF-7 cells of constitutively active PKC delta but not of PKC's eta or alpha or epsilon to enhance p21(WAFl/CIP1) promoter activity. These results suggest that PKC delta plays a fundamental role in the regulation of growth in estrogen receptor positive breast cancer cells.
Shanmugam
M
M
Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Krett
N L
NL
Maizels
E T
ET
Murad
F M
FM
Rosen
S T
ST
Hunzicker-Dunn
M
M
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D003600:Cytosol / Q000201:enzymology; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D017830:Octoxynol / Q000494:pharmacology; D010957:Plasmids; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D014162:Transfection; D014407:Tumor Cells, Cultured
D000098:Acetophenones; D001578:Benzopyrans; C493956:CDKN1A protein, human; D002273:Carcinogens; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003902:Detergents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D017830:Octoxynol; C085746:rottlerin; D008156:Luciferases; C497260:Prkcd protein, rat; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate