Role of peroxisome proliferator activated receptor gamma and 15deoxy-Delta(12,14)prostaglandin J(2) in the growth and survival of breast cancer cells.

摘要

Peroxisome proliferator activated receptor gamma (PPARγ) is a member of the ligand-activated family of nuclear hormone transcription factors that plays a critical role in cellular growth and homeostasis. PPARγ is activated by several structurally distinct compounds including oxidized derivatives of arachidonic acid metabolism. The endogenous ligand of PPARγ has not yet been identified, however, the J series prostanoid 15deoxyΔ 12,14PGJ₂ (15dPGJ₂) is the most potent transcriptional activator of peroxisome proliferator activated receptor response element (PPRE) containing genes. We characterized the influence of the bioactive J series prostaglandins on breast cancer cell growth. We showed that 15dPGJ₂ induces apoptosis in breast cancer cells and block tumorigenesis in a mouse model. A growing body of literature showed that PPARγ agonists induce distinct and differing biological responses. Thus, we reviewed the literature up to December 1999 and showed that PPARγ agonists, including 15dPGJ ₂, could increase cellular proliferation, induce differentiation or induce apoptosis in a variety of cancer cell types. None of the studies cited in the review, however, reported all of the observed biological responses in the same cell line. Thus, we showed that 15dPGJ₂ induces all of these important and seemingly opposite biological responses in a single breast cancer cell line. In addition, using differential gene display technology, we showed that the biological effects induced by 15dPGJ₂ require transcription of new gene products, and blocking gene transcription abrogated 15dPGJ₂-induced apoptosis. However, mounting evidence in the literature suggested that some of the biologic responses induced by 15dPGJ₂ are independent of PPARγ activation. Using selective pharmacologic PPARγ agonists and antagonists and genetic mutants of PPARγ we showed that 15dPGJ₂-induced apoptosis is independent of PPARγ expression in breast cancer cells. This raised the critical question of the mechanism by which 15dPGJ₂ induces apoptosis. Recent data suggested that cyclopentenone prostaglandins could induce oxidative stress in cancer cells. Thus, using pro- and anti-oxidants and mass spectrometry we showed that 15dPGJ ₂ induces a rapid oxidative burst that can overwhelm the antioxidant responses of cancer cells, leading to apoptosis, and we identified some of the major lipid oxidation products induced by 15dPGJ₂ which may be candidate molecules for further study.