Prostaglandin A2 (
PGA2) potently inhibits cell proliferation and suppresses
tumor growth in vivo, but little is known regarding the molecular mechanisms mediating these effects. Here we demonstrate that treatment of
breast carcinoma MCF-7 cells with
PGA2 leads to G1 arrest associated with a dramatic decrease in the levels of
cyclin D1 and
cyclin-dependent kinase 4 (cdk4) and accompanied by an increase in the expression of p21. We further show that these effects occur independent of cellular p53 status. The decline in
cyclin D and
cdk4 protein levels is correlated with loss in cdk4
kinase activity, cdk2 activity is also significantly inhibited in PGA2-treated cells, an effect closely associated with the upregulation of p21. Immunoprecipitation experiments verified that p21 was indeed complexed with cdk2 in PGA2-treated cells. Additional experiments with synchronized MCF-7 cultures stimulated with serum revealed that treatment with
PGA2 prevents the progression of cells from G1 to S. Accordingly, the
kinase activity associated with cdk4,
cyclin E, and cdk2 immunocomplexes, which normally increases following serum addition, was unchanged in PGA2-treated cells. Furthermore, the
retinoblastoma protein (Rb), a substrate of cdk4 and cdk2 whose phosphorylation is necessary for cell cycle progression, remains underphosphorylated in PGA2-treated serum-stimulated cells. These findings indicate that
PGA2 exerts its growth-inhibitory effects through modulation of the expression and/or activity of several key G1 regulatory
proteins. Our results highlight the chemotherapeutic potential of
PGA2, particularly for suppressing growth of
tumors lacking p53 function.