Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

15-deoxy-PGJ2 inhibits breast cancer cell proliferation via peroxisome proliferator activated receptor gamma activation

C Clay BS, FH Chilton PhD

Wake Forest University School of Medicine, Winston-Salem, NC,

AIMS: The nuclear steroid hormone receptor, Peroxisome Proliferator Activated Receptor gamma (PPAR gamma), is a transcription factor that drives expression of specific genes when activated by naturally-occurring metabolites of arachidonic acid. A derivative of prostaglandin D2 (PGD2) metabolism, 15-deoxy PGJ2 (15dPGJ2) has been shown to negatively regulate NF kappa-B dependent gene transcription and positively regulate PPAR gamma activity. METHODS & RESULTS: Using the synthetic PPAR gamma agonists, troglitazone and prostaglandin 15dPGJ2, we initially demonstrated that activation of PPAR gamma halts cell cycle progression and induces apoptosis of breast cancer cells. These biological responses were associated with increased expression of the cell cycle regulatory protein, p53, and of the cyclin dependent kinase inhibitors, p21 and p27. Several genes that were upregulated by PPAR gamma activation (p21, p27, and p53) were also found to contain a putative PPAR gamma response element (PPRE). Inhibition of RNA or protein synthesis, using actinomycin D or cycloheximide, respectively, blocked apoptosis induced by 15dPGJ2. Furthermore, a dominant negative mutant of PPAR gamma inhibited transcriptional activity. CONCLUSIONS: Taken together, these data suggest that PPAR gamma is an important signal in the regulation of cancer cell growth and may be an important therapeutic target for the treatment of breast cancer.

KEY WORDS: Nuclear Receptors, Apoptosis, Cell Proliferation.

For more information, contact

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on satellite symposium.