The nutritional flavanone naringenin triggers antiestrogenic effects by regulating estrogen receptor α-palmitoylation

Naringenin ( Nar) is a component of fruits and vegetables associated with healthful benefits, such as in osteoporosis, cancer, and cardiovascular diseases. These protective effects have been linked with Nar antiestrogenic as well as estrogenic activities. Previous studies indicate that Nar impaired estrogen receptor ( ER) alpha signaling by interfering with ER alpha- mediated activation of ERK and phosphoinositide 3- kinase signaling pathways in the absence of effects at the transcriptional level. The present studies evaluated the hypothesis that these Nar antagonistic effects occur at the level of the plasma membrane. Our results indicate that Nar induces ER alpha depalmitoylation faster than 17 beta- estradiol, which results in receptor rapid dissociation from caveolin- 1. Furthermore, Nar impedes ER alpha to bind adaptor ( modulator of nongenomic actions of the ER) and signaling ( c-Src) proteins involved in the activation of the mitogenic signaling cascades ( i. e. ERK and phosphoinositide 3- kinase). On the other hand, Nar induces the ERdependent, but palmitoylation- independent, activation of p38 kinase, which in turn is responsible for Nar-mediated antiproliferative effects in cancer cells. Altogether, these data highlight new ER-dependent mechanisms on the root of antiproliferative and antiestrogenic effects of Nar. Moreover, the different modulation of ER alpha palmitoylation exerted by different ligands represents a pivotal mechanism that drives cancer cell to proliferation or apoptosis.