Earlyde NovoGene Expression Is Required for 15-Deoxy-Δ12,14-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(PGJ2) metabolism, 15-deoxy-Δ12,14-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 15dPGJ2effects can be mediated by PPARγ-dependent and PPARγ-independent mechanisms. Here we report that 15dPGJ2regulates early gene expression critical to apoptosis. Specifically, 15dPGJ2induces 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 p21Waf1/Cip1(p21). Inhibition of RNA or protein synthesis abrogates apoptosis induced by 15dPGJ2in breast cancer cells but potentiates apoptosis induced by tumor necrosis factor-α or CD95/Fas ligand. Additionally, 15dPGJ2induces caspase activation that is blocked by peptide caspase inhibitors. These data show thatde novogene 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.