Potential Therapeutic Role of J Series Prostaglandins in PPAR-gamma Mediated Treatment of Breast Cancer

摘要

Naturally occurring derivatives of arachidonic acid metabolism are potent and effective activators of PPAR-gamma. The most potent of these derivatives is 15deoxy-delta(12,14)PGJ2 (15dPGJ2), the dehydration and isomerization product of prostaglandin D2 (PGD2). 15dPGJ2 induces PPAR-gamma mediated transcriptional activation leading to the synthesis of critical gene products involved in cell cycle arrest and apoptosis. of these gene products, expression of the cyclin dependent kinase inhibitors, p21 and p27, is associated with marked cell cycle arrest with subsequent apoptosis involving caspase-3. However, apoptosis induced by 15dPGJ2 is unlikely to be PPAR-gamma mediated as demonstrated by studies with dominant negative forms of this receptor. To further elucidate how AA derivatives such as 15dPGJ2 induce apoptosis in breast cancer cells investigations into AA metabolic pathways were undertaken. We demonstrate that intracellular accumulation of AA induces apoptosis in cancer cells by activating the AP-1 family of nuclear transcription factors. Given the anti-cancer efficacy of therapies which alter AA metabolism, such as NSAIDs, further investigation into 15dPGJ2 and other facets of the AA metabolic pathway are warranted.