Dataset Information

Cancer-preventive rexinoid modulates neutral lipid contents of mammary epithelial cells through a peroxisome proliferator-activated receptor ?-dependent mechanism.

ABSTRACT: Synthetic rexinoids effectively suppress both estrogen receptor-positive and estrogen receptor-negative mammary tumors in animal models, which makes them prime candidates for a novel class of cancer-preventive agents. When used in combination with chemotherapy for non-small-cell lung cancer, the rexinoid bexarotene was most effective for patients who developed hypertriglyceridemia as a side effect. Although serum triglycerides originate from the liver, the effect of bexarotene on lipogenesis in breast epithelial cells is not known. Gene expression studies with normal mammary epithelial cells indicated that rexinoids modulate lipid metabolism, particularly enzymes involved in triglyceride synthesis. High-content analysis revealed dose-dependent accumulation of neutral lipids within adipocyte differentiation-related protein-associated cytoplasmic lipid droplets after long-term bexarotene treatment. Bexarotene also induced mRNA and protein levels for peroxisome proliferator-activated receptor (PPAR) ?, whereas selective knockdown of PPAR? attenuated the induction of both lipid droplets and adipocyte differentiation-related protein. Pharmacological activation of PPAR?, but not PPAR? or retinoic acid receptors, effectively induced lipid accumulation. Furthermore, the combination of the PPAR? agonist rosiglitazone with bexarotene synergistically suppressed the growth of human mammary epithelial cells and revealed a strong, nonlinear, inverse correlation of cell growth with lipid droplet accumulation in the cell population. These findings indicate that rexinoids activate a lipogenic program in mammary epithelial cells through a retinoid X receptor/PPAR?-mediated mechanism. It is noteworthy that combining low doses of bexarotene with the PPAR? agonist rosiglitazone provides effective growth suppression of mammary epithelial cells, potentially dissociating systemic adverse effects associated with standard bexarotene treatment from the antiproliferative effects on mammary epithelium.

SUBMITTER: Uray IP

PROVIDER: S-EPMC3263950 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cancer-preventive rexinoid modulates neutral lipid contents of mammary epithelial cells through a peroxisome proliferator-activated receptor γ-dependent mechanism.

Uray Iván P IP Rodenberg Jennifer M JM Bissonnette Reid P RP Brown Powel H PH Mancini Michael A MA

Molecular pharmacology 20111103 2

Synthetic rexinoids effectively suppress both estrogen receptor-positive and estrogen receptor-negative mammary tumors in animal models, which makes them prime candidates for a novel class of cancer-preventive agents. When used in combination with chemotherapy for non-small-cell lung cancer, the rexinoid bexarotene was most effective for patients who developed hypertriglyceridemia as a side effect. Although serum triglycerides originate from the liver, the effect of bexarotene on lipogenesis in ...[more]

PMID: 22053058

Similar Datasets

Project description:Although glucocorticoids (GC) represent the most frequently used immunosuppressive drugs, their effects are still not well understood. In our previous studies, we have shown that treatment of monocytes with GC does not cause a global suppression of monocytic effector functions, but rather induces differentiation of a specific anti-inflammatory phenotype. The anti-inflammatory role of peroxisome proliferator-activated receptor (PPAR)-? has been extensively studied during recent years. However, a relationship between GC treatment and PPAR-? expression in macrophages has not been investigated so far. Studies using PPAR-?-deficient mice have frequently provided controversial results. A potential reason is the use of primary cells, which commonly represent inhomogeneous populations burdened with side effects and influenced by bystander cells. To overcome this constraint, we established ER-Hoxb8-immortalized bone marrow-derived macrophages from Ppargfl/fl and LysM-Cre Ppargfl/fl mice in this study. In contrast to primary macrophages, the ER-Hoxb8 system allows the generation of a homogeneous and well-defined population of resting macrophages. We could show that the loss of PPAR-? resulted in delayed kinetic of differentiation of monocytes into macrophages as assessed by reduced F4/80, but increased Ly6C expression in early phases of differentiation. As expected, PPAR-?-deficient macrophages displayed an increased pro-inflammatory phenotype upon long-term LPS stimulation characterized by an elevated production of pro-inflammatory cytokines TNF-?, IL1-?, IL-6, IL-12 and a reduced production of anti-inflammatory cytokine IL-10 compared to PPAR-? WT cells. Moreover, PPAR-?-deficient macrophages showed impaired phagocytosis. GC treatment of macrophages led to the upregulation of PPAR-? expression. However, there were no differences in GC-induced suppression of cytokines between both cell types, implicating a PPAR-?-independent mechanism. Intriguingly, GC treatment resulted in an increased in vitro migration only in PPAR-?-deficient macrophages. Performing a newly developed in vivo cell-tracking experiment, we could confirm that GC induces an increased recruitment of PPAR-? KO, but not PPAR-? WT macrophages to the site of inflammation. Our findings suggest a specific effect of PPAR-? on GC-induced migration in macrophages. In conclusion, we could demonstrate that PPAR-? exerts anti-inflammatory activities and shapes macrophage functions. Moreover, we identified a molecular link between GC and PPAR-? and could show for the first time that PPAR-? modulates GC-induced migration in macrophages.

Dataset Information

Cancer-preventive rexinoid modulates neutral lipid contents of mammary epithelial cells through a peroxisome proliferator-activated receptor ?-dependent mechanism.

Publications

Cancer-preventive rexinoid modulates neutral lipid contents of mammary epithelial cells through a peroxisome proliferator-activated receptor γ-dependent mechanism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets