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

Abstract

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-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 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.