Early de Novo Gene Expression Is Required for 15-Deoxy-Δ ^12,14-prostaglandin J₂-induced Apoptosis in Breast Cancer Cells

Cyclopentenone prostaglandin derivatives of arachidonic acid are potent inducers of apoptosis in a variety of cancer cell types. Several investigators have shown that the terminal derivative of prostaglandin J₂ (PGJ ₂) metabolism, 15-deoxy-Δ^12,14-PGJ₂ (15dPGJ₂), induces apoptosis in breast cancer cells and is a potent activator of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ), but 15dPGJ₂ effects can be mediated by PPARγ-dependent and PPARγ-independent mechanisms. Here we report that 15dPGJ₂ regulates early gene expression critical to apoptosis. Specifically, 15dPGJ₂ induces potent and irreversible S phase arrest that is correlated with expression of genes critical to cell cycle arrest and apoptosis, including the cyclin-dependent kinase inhibitor p21 ^Waf1/Cip1 (p21). Inhibition of RNA or protein synthesis abrogates apoptosis induced by 15dPGJ₂ in breast cancer cells but potentiates apoptosis induced by tumor necrosis factor-α or CD95/Fas ligand. Additionally, 15dPGJ₂ induces caspase activation that is blocked by peptide caspase inhibitors. These data show that de novo gene transcription is necessary for 15dPGJ₂-induced apoptosis in breast cancer cells. Critical candidate genes are likely to be revealed through analysis of differential cDNA array expression.