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Although discovered in 2000, neuroglobin (Ngb) functions are still uncertain. A contribution to the role played by Ngb in neurons could certainly derive from the identification of Ngb endogenous modulators. Here, we evaluate the possibility that Ngb could be regulated by 17β-estradiol (E 2) signaling in both SK-N-BE human neuroblastoma cell line and mouse hippocampal neurons. 1 nM E2 rapidly induced a 300% increase in Ngb levels in both models. The E2 effect was specific, being not induced by testosterone or dihydrotestosterone. The E2-induced Ngb increase requires estrogen receptor (ER) β, but not ERα, as evaluated by the mimetic effect of ERβ-specific agonist DPN and by the blockage of E 2 effect in ERβ-silenced SK-N-BE cells. Furthermore, both rapid (15 min) ERβ-dependent activation of p38/MAPK and transcriptional ERβ activity were required for the estrogenic regulation of Ngb. Finally, E 2 exerted a protective effect against H2O 2-induced neuroblastoma cell death which was completely prevented in Ngb-silenced cells. Overall, these data suggest that Ngb is part of the E 2 signaling mechanism that is activated to exert protective effects against H2O2-induced neurotoxicity. Copyright © 2011 S. Karger AG, Basel.

Cleome arabica L. (Capparidaceae) is a desert plant widely distributed in the North part of Africa whose leaves are used in traditional medicine as a sedative for abdominal and rheumatic pains.The anticancer activity of methanol Cleome arabica leaf extracts (CALE) is investigated in different human cancer cell lines.Five different human cancer cell lines, representative of the most common cancers in Western countries (i.e., breast adenocarcinoma, colon carcinoma, neuroblastoma, hepatoma, cervix carcinoma) were treated with different concentrations of CALE (i.e., 1, 5, 10, 25, 50, 100 and 200 µg/ml). Cell viability and cell cycle were measured by using a hemocytometer chamber and a cytofluorimeter, respectively. Epidermal growth factor (EGF) was used as a positive control. Western blots were performed to evaluate the CALE effects on pathways involved in cell growth regulation and on apoptotic cascade activation.Our results confirm that CALE has a high content of polyphenolic compounds (i.e., 32.21 ± 3.44%), mainly as flavonoids (24.56 ± 4.67%). In all tested cell lines CALE treatment reduces cell number in a dose-dependent manner (ED50 = 175 ± 30 µg/ml). CALE (100 and 200 µg/ml) increases by three-fold the activation of the apoptotic cascade involving caspase-3 activation and the cleavage of its substrate poly(ADP-ribose) polymerase (PARP). Intriguingly, CALE treatment (200 µg/ml) also blocks EGF-induced cell growth by preventing the growth factor-triggered AKT and ERK phosphorylation. As a whole, these data strongly suggest that CALE possesses anticancer effects in all tested cancer cell lines.

Fruit and vegetable consumption has generally been associated with the prevention or suppression of cancer. However, food could contain a multitude of chemicals (e.g., bisphenol A; BPA) that could synergize or antagonize the effects of diet-derived compounds. Remarkably, food containers (e.g., water and infant bottles) are the largest source of exposure to BPA for human beings. Here, the effects of the coexposure of naringenin (Nar, 1.0 × 10−9 M to 1.0 × 10−4 M) and BPA (1.0 × 10−5 M) in estrogen-dependent breast cancer cell lines expressing (i.e., MCF-7 and T47D) or not expressing (i.e., MDA-MB-231) estrogen receptor α (ERα) are reported. Although both Nar and BPA bind to ERα, they induce opposite effects on breast cancer cell growth. BPA induces cell proliferation, whereas Nar only decreases the number of ERα-positive cells (i.e., MCF-7 and T47D). Notably, even in the presence of BPA, Nar impairs breast cancer cell proliferation by activating caspase-3. The molecular pathways involved require p38 activation, whereas, the BPA-induced AKT activation is completely prevented by the Nar treatment. As a whole, Nar maintains its proapoptotic effects even in the presence of the food contaminant BPA, thus, enlarging the chemopreventive potential of this flavanone. © 2012 IUBMB IUBMB Life, 64(8): 690–696, 2012

Bisphenol A (BPA), a prototype of endocrine disruptors, mimics 17β-estradiol (E2)-induced proliferation in several cancer cells by binding to estrogen receptor α (ERα). However, scarce and conflicting data are available concerning the effect of BPA on estrogen receptor β (ERβ)-mediated functions. Here, the detailed analysis of the effect of BPA, alone or in combination with E2, on ERβ-mediated cellular functions is reported in ERβ-expressing colon cancer cell line. BPA binds to ERβ without activating any receptor activities. On the other hand, BPA inhibits E2-induced genomic activity of ERβ as well as ERβ extra-nuclear activities (i.e., ERβ:p38 association and p38 activation). As a consequence, BPA impairs the E2-induced activation of the apoptotic cascade which is at the root of the protective role played by the hormone against colon cancer growth. Thus, women may be considered a highly susceptible population with an increased risk of colon cancers after BPA exposures. © 2010 IUBMB IUBMB Life, 62(9): 684–687, 2010

Sexual dimorphism, detectable in vascular smooth muscle cells freshly isolated from aorta of male and female rats, is associated with a different susceptibility to radiation-induced apoptosis. In this work we investigated the mechanism underlying this difference and discovered that, in comparison with cells from male rats, cells from female rats show adhesion-associated resistance to apoptosis, the so called anoikis resistance. This is apparently due to a more adhering phenotype, characterized by a well organized actin microfilament cytoskeleton and to an increased phosphorylated focal adhesion kinase, and, more importantly, to a higher propensity to undergo survival by autophagy.

The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant or pro-oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin-induced anti-proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor alpha (ERalpha; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H(2)O(2)-induced ROS production both in the presence and in the absence of ERalpha. However, this flavonoid induces the activation of p38/MAPK, leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage only in the presence of ERalpha. Notably, no down-regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings suggest that quercetin results in HeLa cell death through an ERalpha-dependent mechanism involving caspase- and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.

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 ERalpha-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 ERalpha depalmitoylation faster than 17beta-estradiol, which results in receptor rapid dissociation from caveolin-1. Furthermore, Nar impedes ERalpha 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 ER-dependent, 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 ERalpha palmitoylation exerted by different ligands represents a pivotal mechanism that drives cancer cell to proliferation or apoptosis.