Role of Aquaporins in Breast Cancer Progression and Metastasis

There are various limitations regarding the current pharmacological options for the treatment of breast cancer in terms of efficacy, target selectivity, side effect profile and survival. Endocrine-based therapy for hormone-sensitive cancers such as that of the breast is one of the most effective and well-tolerated therapeutic options but is hampered by either intrinsic or acquired resistance, resulting in a more aggressive form of the disease. It is generally agreed that this process occurs in parallel with cellular transition from epithelial to mesenchymal phenotype (EMT), with consequent enhancement of proliferative capacity, migrative ability and invasive potential. Aquaporins (AQPs) represent a large family of water channel proteins which are widely distributed in various tissues and which play a role in the physiological maintenance of the extracellular environment particularly to regulate electrolyte-water balance. Accumulating evidence shows that expression of several AQPs is modulated in cancer tissues, and this correlates with tumor grade. AQPs 1 and 3–5 are also involved in breast cancer invasion, through modulating the activity of various growth factors, signaling molecules and proteolytic enzymes. We review current data on the involvement of these proteins in processes associated with malignant progression and discuss possible applications of AQP-based therapy as an effective means of inhibiting cancer cells from metastasizing

Minocycline synergizes with corticosteroids in reducing colitis severity in mice via the modulation of pro-inflammatory molecules

Background: A few studies have highlighted the anti-inflammatory properties of minocycline in reducing colitis severity in mice, but its molecular mechanism is not fully understood. The aim of this study was to determine the anti-inflammatory properties of minocycline and the expression/activity profiles of molecules involved in pro-inflammatory signaling cascades, cytokines, and molecules involved in the apoptotic machinery. The synergistic effect between minocycline and corticosteroids was also evaluated.Methods: The effects of various treatment approaches were determined in mice using the dextran sulfate sodium (DSS) colitis model at gross and microscopic levels. The expression/activity profiles of various pro- or anti-inflammatory molecules were determined using Western blotting and polymerase chain reaction (PCR).Results: Minocycline treatment significantly reduced colitis severity using prophylactic and treatment approaches and produced a synergistic effect with budesonide and methylprednisolone in reducing the active state of colitis. This was mediated in part through reduced colonic expression/activity of pro-inflammatory molecules, cytokines, proteins involved in the apoptotic machinery, and increased expression of the anti-inflammatory cytokine IL-10.Conclusion: Minocycline synergizes with corticosteroids to reduce colitis severity, which could reduce their dose-dependent side effects and treatment cost. The reduction in colitis severity was achieved by modulating the expression/activity profiles of various pro- and anti-inflammatory signaling molecules, cytokines, and molecules involved in the apoptotic machinery

α7 Nicotinic Acetylcholine Receptor Interaction with G Proteins in Breast Cancer Cell Proliferation, Motility, and Calcium Signaling

Chronic smoking is a primary risk factor for breast cancer due to the presence of various toxins and carcinogens within tobacco products. Nicotine is the primary addictive component of tobacco products and has been shown to promote breast cancer cell proliferation and metastases. Nicotine activates nicotinic acetylcholine receptors (nAChRs) that are expressed in cancer cell lines. Here, we examine the role of the α7 nAChR in coupling to heterotrimeric G proteins within breast cancer MCF-7 cells. Pharmacological activation of the α7 nAChR using choline or nicotine was found to increase proliferation, motility, and calcium signaling in MCF-7 cells. This effect of α7 nAChR on cell proliferation was abolished by application of Gαi/o and Gαq protein blockers. Specifically, application of the Gαi/o inhibitor pertussis toxin was found to abolish choline-mediated cell proliferation and intracellular calcium transient response. These findings were corroborated by expression of a G protein binding dominant negative nAChR subunit (α7345-348A), which resulted in significantly attenuating calcium signaling and cellular proliferation in response to choline. Our study shows a new role for G protein signaling in the mechanism of α7 nAChR-associated breast cancer growth

Impact of the Group IV Protein Tyrosine Kinase, Fer, on Intestinal Inflammation and Neutrophil Function

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Anti-Inflammatory Properties of the Enaminone E121 in the Dextran Sulfate Sodium (DSS) Colitis Model.

Enaminones are synthetic compounds with an established role in the prevention of various forms of seizures. Recent evidence suggests potent anti-tussive, bronchodilation and anti-inflammatory properties. Pre-treatment with particularly E121 compound resulted in a decrease in leukocyte recruitment in the ovalbumin induced-model of asthma, immune cell proliferation and cytokine release in vitro. We hypothesize that E121 might serve as a therapeutic potential in intestinal inflammation through modulating immune cell functions.Colitis was induced by daily dextran sulfate sodium (DSS) administration for 5 days, and its severity was determined by gross and histological assessments. The plasma level of various cytokines was measured using flow cytometry-based assay. The colonic expression/ phosphorylation level of various molecules was determined by immunofluorescence and western blotting. The effects of E121 treatment on in vitro neutrophil chemotaxis (under-agarose assay), superoxide release (luminol oxidation assay) and apoptosis (annexin V/7AAD) were also determined.DSS-induced colitis in mice was significantly reduced by daily E121 treatment (30-100 mg/kg) at gross and histological levels. This effect was due to modulated plasma levels of interleukin (IL-2) and colonic expression levels of various signaling molecules and proteins involved in apoptosis. In vitro neutrophil survival, chemotaxis, and superoxide release were also reduced by E121 treatment.Our results indicate important anti-inflammatory actions of E121 in the pathogenesis of IBD

Effect of E121 treatment on colitis severity.

<p>Panel A shows % body weight changes in DSS treated mice alone or receiving vehicle (solid circles and squares, black lines), or E121 treated mice (red lines) compared to untreated (UT) mice receiving tap water only (open circle, hatched green line). Panels B and C show % of circulating neutrophils and lymphocytes respectively determined at day 5 post colitis induction in DSS treated mice alone or receiving vehicle (solid bars) or E121 treated mice (hatched bars) compared to UT group (open bars). Colon length (panel D) and thickness (panel E) was determined in all groups. Histobars represent means ± SEM for 6 mice in each group. Asterisks denote significant difference from UT mice with p<0.05 (*), # denotes significant difference from DSS alone and DSS/i.p vehicle treated mice with p<0.05.</p