Accession Number:

ADA394211

Title:

A Potential Therapeutic Role of J Series Prostaglandins in PPAR(gamma) Mediated Treatment of Breast Cancer

Descriptive Note:

Annual summary15 May 2000-14 May 2001

Corporate Author:

WAKE FOREST UNIV WINSTON-SALEM NC SCHOOL OF MEDICINE

Report Date:

2001-06-01

Pagination or Media Count:

11.0

Abstract:

Cyclopentenone prostaglandin derivatives of arachidonic acid are promising molecules in the fight against cancer, but their mechanism of action is not well understood. Several investigators have shown that the terminal derivative of prostaglandin J2 PGJ2 metabolism 15deoxy Delta PGJ2 15dPGJ2 is a potent activator of the nuclear hormone receptor peroxisome proliferator activated receptor gamma PPAR gamma, but 15dPGJ2 effects can be mediated by PPAR gamma-dependent and PPAR gamma-independent mechanisms. A candidate PARR gamma independent mechanism is 15dPGJ2 induced inhibition of NF Kappa B via covalent modification of IKK, I kappa B alpha and the DNA binding domain of NF Kappa B. We have shown previously that 15dPGJ2 potently induces apoptosis of breast cancer cells and that 15dPCJ2 regulates gene expression critical to apoptosis. Specifically, 15dPGJ2 induces potent and irreversible S-phase arrest that is correlated with 2-fold increased expression of at least 20 of 1,176 genes as determined by cDNA differential display. Inhibition of RNA synthesis, using actinomycin D, or protein synthesis, using cycloheximide, abrogates apoptosis induced by 15dPGJ2 in breast cancer cells. Additionally, caspase-3 activation follows the induction of gene transcription and the peptide inhibitor ZVAD-fmk blocks apoptosis. These data show that de novo gene transcription is necessary for 15dPGJ2 induced apoptosis in breast cancer cells, that inhibition of NF kappa B plays a minor role in 15dPGJ2 induced apoptosis and identifies cyclopentenone prostaglandins and potential therapeutic molecules for PPAR gamma mediated apoptosis in breast cancer.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE