Targeting Peroxisome Proliferator-Activated Receptor ? to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPAR? is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPAR? in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPAR? expression. Activation of PPAR? by a specific agonist, pioglitazone, selectively blocked the induction of TNF? expression by E2, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNF? expression by pioglitazone was mainly mediated by transrepression of nuclear factor-?B (NF-?B) DNA-binding activity. A novel finding was that NF-?B functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-?B inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E2-induced apoptosis in MCF-7:2A cells. Depletion of PPAR? by siRNA or the PPAR? antagonist T0070907 accelerated E2-induced apoptosis, with activation of NF-?B-dependent TNF? and oxidative stress. For the first time, we demonstrated that PPAR? is a growth signal and has potential to modulate NF-?B activity and oxidative stress in E2-deprived breast cancer cell lines. All of these findings suggest that anti-PPAR? therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.

SUBMITTER: Fan P 

PROVIDER: S-EPMC6279501 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature