Magnitude of peroxisome proliferator-activated receptor-gamma activation is associated with important and seemingly opposite biological responses in breast cancer cells

Citation
Ce. Clay et al., Magnitude of peroxisome proliferator-activated receptor-gamma activation is associated with important and seemingly opposite biological responses in breast cancer cells, J INVES MED, 49(5), 2001, pp. 413-420
Citations number
52
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
Journal title
JOURNAL OF INVESTIGATIVE MEDICINE
ISSN journal
10815589 → ACNP
Volume
49
Issue
5
Year of publication
2001
Pages
413 - 420
Database
ISI
SICI code
1081-5589(200109)49:5<413:MOPPRA>2.0.ZU;2-E
Abstract
Background. The nuclear receptor peroxisome proliferator-activated receptor -gamma (PPAR gamma) has become a potential target for the prevention and tr eatment of breast cancer. However, recent in vitro and in vivo studies have raised the question of whether activation of PPAR gamma leads to the promo tion or reduction of tumor formation. Studies using several cancer cell lin es, animal models, and a variety of PPAR gamma agonists have shown discorda nt results, including changes in cellular proliferation, differentiation, a nd apoptosis of cancer cells and tumors. Methods: We studied the effects of low-, moderate-, and high-dose treatment of the PPAR gamma ligands 15-deoxy-Delta (12,14)prostaglandin J(2) (15dPGJ (2)) and troglitazone (TGZ) on parameters of cell growth, differentiation, and apoptosis in the epithelial breast cancer cell line MDA-MB-231. Results: The biologic effects of these compounds depend largely on ligand c oncentration and the degree of PPAR gamma activation. For example, low conc entrations of 15dPGJ(2) (<2.5 muM) and TGZ (<5 muM) increased cellular prol iferation, but concentrations of 15dPGJ(2) greater than or equal to 10 muM and of TGZ at 100 muM blocked cell growth. TGZ (100 muM) slowed cell cycle progression, and 15dPGJ(2) (10 muM) caused an S-phase arrest in the cell cy cle and induced morphological characteristics consistent with apoptosis. Ex pression of CD36, a marker of differentiation in these cells, was induced b y 2.5 muM 15dPGJ(2) or 5 to 100 muM TGZ. However, higher concentrations of 15dPGJ(2) did not alter CD36 expression. Transcriptional activation studies demonstrated that 15dPGJ(2) is a more potent PPAR gamma ligand than TGZ. R egardless of the ligand used, though, low transcriptional activation correl ated with an increased cellular proliferation, whereas higher levels of act ivation correlated with cell cycle arrest and apoptosis. Conclusions: PPAR gamma activation induces several important and seemingly opposite changes in neoplastic cells, depending on the magnitude of PPAR ga mma activation. These data may explain, at least in part, some of the disco rdant results previously reported.