Nitric oxide impairs the 17β-estradiol-induced apoptosis in human colon adenocarcinoma cells

Abstract

Nitric oxide (NO) and 17b-estradiol (E2) are both important in gastrointestinal health and disease. NO contributes to gastrointestinal motility as well as to inflammation and carcinogenic processes. By contrast, E2 reduces the incidence of colon adenoma and carcinoma by about 30%. We report the genomic and non-genomic E2-estrogen receptor (ER) b-induced effects in human colon adenocarcinoma. The effect of NO on ERb activities was also assessed. The E2-ERbdependent gene transcription was inhibited by exogenous NO, whereas some non-genomic E2-dependent effects (e.g. p38/MAP kinase), important for the activation of the apoptotic cascade, were unaffected by NO. However, NO impaired the E2-induced pro-apoptotic cascade in human colon adenocarcinoma cells by inhibiting caspase-3. The effects of NO may reflect chemical modification(s) of Cys residues present in the DNA recognition domain of ERb as well as in the caspase-3 active site. On the whole, high NO concentrations suppressed the E2 protective effects in the gastrointestinal tract, suggesting that the caspase-dependent apoptotic cascade may become critical under conditions of high redox stress such as occur under specific activation of the immune system by chronic infections or pathogen challenge.

Estrogen Signaling Multiple Pathways to Impact Gene Transcription

“…Geraldes and coworkers reported that E2 reduces ERK activity through ER stimulation in porcine smooth muscle cells [134]. We have recently reported the ability of the ER -E2 complex to activate the p38 member of MAPK family, but not ERK or AKT, in human colon cancer cells [81,135]. Although the scarce information does not allow a complete discussion on the contribution of ER in E2-induced rapid signals, these data indicate that also ER could originate cell-specific signal transduction cascade.…”

“…Besides these data, much evidence favors the idea that the membrane-localized ER is the same protein as the nuclear-localized receptor [72,80,133,143,144]. Even if the definitive proof that membrane and nuclear ER are the same protein requires isolation and "sequencing" of the two receptor pools, ER and ER must be considered a population of protein(s) which localization in the cell is able to dynamically change, shuttling from membrane to cytosol and to the nucleus, depending on ligand binding [87,97,135,145].…”

Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation

“…The ERs-devoid human cervix epithelioid carcinoma cell line (HeLa; Marino et al 2002) and the ERb containing human colon adenocarcinoma cells (DLD-1; Marino et al 2006) were used as experimental models. Cells were routinely grown in air containing 5% CO 2 in modified, phenol red-free, DMEM (HeLa cells) or RPMI-1640 (DLD-1 cells) media, containing 10% (v/v) charcoal-stripped fetal calf serum, Lglutamine (2 mM), gentamicin (0.1 mg/ml), and penicillin (100 U/ml).…”

“…In DLD-1 cells, the rapid, persistent E2-induced activation of the p38/MAPK pathway is sufficient and necessary for E2-induced apoptosis (i.e., caspase-3 activation and PARP cleavage; Marino et al 2006). We next determined whether ERb palmitoylation could have an impact on these rapid non-genomic ERb activities.…”

Estrogen and gastrointestinal malignancy

“…It is felt that protein kinase C is a most likely involved in mediation of this rapid action. Further putative mechanisms of actions include p38 mitogen activated protein kinase leading to caspase-3 dependant apoptosis 79 , increased expression of vitamin D receptor mediated by mitogen activated protein kinase 1 or 3 80 or ER β activation of p38 mitogen activated protein kinase cascade 81 . Unlike esophagus, stomach or gallbladder, evidence of protective effects of estrogen against colorectal cancer is compelling.…”