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