Contribution of protein kinase A and protein kinase C signalling pathways to the regulation of HSD11B2 expression and proliferation of MCF-7 cells.
Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the regulation of 11beta-hydroxysteroid dehydrogenase type II (HSD11B2) gene expression was investigated in human breast cancer cell line MCF-7. Treatment of the cells with an adenylyl cyclase activator, forskolin, known to stimulate the PKA pathway, resulted in an increase in HSD11B2 mRNA content. Semi-quantitative RT-PCR revealed attenuation of the effect of forskolin by phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the PKC pathway. It was also demonstrated that specific inhibitors significantly reduced the effect of activators of the two pathways. Stimulation of the PKA pathway did not affect, whereas stimulation of the PKC pathway significantly reduced MCF-7 cell proliferation in a time-dependent manner. A cell growth inhibitor, dexamethasone, at high concentrations, caused a 40% decrease in proliferation of MCF-7 cells and this effect was abolished under conditions of increased HSD11B2 expression. It was concluded that in MCF-7 cells, stimulation of the PKA signal transduction pathway results in the induction of HSD11B2 expression and that this effect is markedly reduced by activation of the PKC pathway. Activation of the PKC pathway also resulted in inhibition of cell proliferation, while activation of the PKA pathway abolished the antiproliferative effect of dexamethasone. These effects might be due to oxidation of dexamethasone by the PKA-inducible HSD11B2.
Rubiś
Błazej
B
Department of Biochemistry and Molecular Biology, University of Medical Sciences, Poznań, Poland.
Grodecka-Gazdecka
Sylwia
S
Lecybył
Remigiusz
R
Ociepa
Marta
M
Krozowski
Zygmunt
Z
Trzeciak
Wiesław H
WH
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005576:Colforsin / Q000494:pharmacology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction
D005576:Colforsin; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C