Relative involvement of protein kinase C and of the estrogen receptor in the cytotoxic action of a population of triphenylethylenes on MCF7 cells as revealed by correspondence factorial (CF) analysis.
A multivariate statistical method, correspondence factorial (CF) analysis, was used to examine the correlations among the protein binding and cell proliferation effects of a series of 36 di- and triphenylethylenes (DPEs and TPEs). The analysis was applied to a study which measured their competition for estradiol binding to cytosol estrogen receptor (ER), their influence on protein kinase C (PKC) activity under different conditions of enzyme activation, their ability to promote the growth of a breast cancer cell line and to inhibit growth at high concentrations (cytotoxicity). The CF analysis revealed several levels of correlation. First, it distinguished those molecules within the population that stimulated rather than inhibited PKC activity. Second, it made apparent a strong correlation between cytotoxicity and inhibition of Ca++ and phosphatidylserine-dependent PKC activity, which was most marked when the enzyme had been activated by diacylglycerol indicating that PKC inhibition under physiological conditions might contribute to the overall cytotoxicity of these compounds. Third, a lower level of correlation was established between competition for ER binding and cytotoxicity. Taken together, the results suggest that MCF7 cells might be most sensitive to a cytotoxic effect of TPEs (via PKC and other targets) when they at the same time decrease estrogen-stimulated proliferation via an ER-mediated antiestrogenic effect.
Ojasoo
T
T
Roussel-Uclaf, Paris, France.
Bignon
E
E
Crastes de Paulet
A
A
Doré
J C
JC
Gilbert
J
J
Miquel
J F
JF
Pons
M
M
Raynaud
J P
JP
D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015999:Multivariate Analysis; D010718:Phosphatidylserines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*; D013343:Styrenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D010718:Phosphatidylserines; D011960:Receptors, Estrogen; D013267:Stilbenes; D013343:Styrenes; D004958:Estradiol; C007518:1,1-diphenylethylene; D011493:Protein Kinase C; C037749:triphenylethylene; D002118:Calcium