Pectasol-C Modified Citrus Pectin targets Galectin-3-induced STAT3 activation and synergize paclitaxel cytotoxic effect on ovarian cancer spheroids.

Here we sought to determine the relationship between STAT3 activity and Galectin-3 (Gal-3) and to investigate the cytotoxic effect of PectaSol-C Modified Citrus Pectin (Pect-MCP) as a specific competitive inhibitor of Galectin-3 (Gal-3) in combination with Paclitaxel (PTX) to kill the ovarian cancer cell SKOV-3 multicellular tumor spheroid (MCTS). To this order, SKOV-3 cells in 2D and 3D cultures were treated with exogenous Gal-3 for the assessment of STAT3 activity. Two-way ANOVA main effect and IC50 of each drug Paclitaxel (PTX) and Pect-MCP or in combination were obtained from MTT assay results. The phosphorylated STAT3 levels, migration, invasion, integrin mRNA and p-AKTser473 levels were assessed in the absence or presence of each drug alone or in combination. Gal-3 expression levels were assessed in human serous ovarian cancer (SOC) specimens and its correlation with different integrin mRNA levels was further assessed. Our results showed that Gal-3 expression level was significantly increased in MCTS compared to monolayer SKOV-3 cells which triggered STAT3 phosphorylation. Moreover, Pect-MCP synergized with PTX to kill SKOV3 MCTS through abrogation of STAT3 activity and reduced expression of its downstream target HIF-1α, reduced integrin mRNA levels, and subsequently decreased AKT activity. There were higher expression levels of Gal-3 in human high-grade SOC specimens compared to the normal ovary and borderline SOC which positively and significantly correlated with α5, ß2 and ß6 integrin mRNA levels. Together, these results revealed for the first time that Pect-MCP could be considered as a potential drug to enhance the PTX effect on ovarian cancer cells MCTS through inhibition of STAT3 activity.

Oxytocin effects on the inhibition of the NF-κB/miR195 pathway in mice breast cancer.

Oxytocin (OT) has the suppressive effects on breast tumor formation and development. We hypothesized that OT through the NF-κB inhibition can induce the miR-195 up-regulation which it can promote the cell apoptosis and inhibit the cell proliferation. Thirty-two BALB/c female mice were equally divided into four groups to study the effects of OT and atosiban (ATO) (an oxytocin receptor antagonist) on the mammary tumor growth. The animal weight, OT plasma concentration, and the tumor weight and volume were measured. Moreover, the tumor-related signaling pathways including NF-κB, miR-195, and Cyclin D1 were evaluated by qPCR assays, and Akt and ERK proteins were assessed by western blot at the end of the study. The volume and weight of tumors were significantly decreased after OT administration. The phosphorylated Akt and ERK expressions were significantly decreased in the OT group compared to the tumor group. In contrast, the dephosphorylated Akt and ERK expressions were significantly increased in the OT group in comparison with the tumor group. The mRNA expressions of miR-195, OTR, and Bax genes were significantly increased, and the mRNA expression of ERα, PI3K, NF-κB, cyclin D1 and Bcl-2 genes were decreased in the OT group in comparison with the tumor group. Interestingly, ATO administration reversed these effects. These results can exhibit a new therapeutic potential for OT on the down-regulation of the NF-κB and up-regulation of miR-195 and consequently, decrease of the tumor volume and weight in a mouse model of breast cancer.

Oxytocin mediates the beneficial effects of the exercise training on breast cancer.

NEW FINDINGS: What is the central question of this study? We hypothesized that potential anti-tumour effects of exercise training might be mediated by oxytocin and explored the underlying mechanisms in a mouse model of breast cancer. What is the main finding and its importance? Interval exercise training, by inducing oxytocin secretion, may reduce the activity of the PI3K/Akt and ERK pathways, and consequently, results in a smaller tumour volume in a mouse model of breast cancer. Exercise training can affect the growth of breast tumours. We hypothesized that exercise training might reduce breast tumour growth by inducing oxytocin (OT) secretion and its related signalling pathways, such as PI3K/Akt and ERK. Therefore, 56 BALB/c mice were equally divided into seven groups to study the effects of OT and atosiban (an oxytocin receptor antagonist) together with interval exercise training on mammary tumour growth, as well as tumour-related signalling pathways, including PI3K/Akt and ERK. Animal weight, OT plasma concentration, tumour weight and volume were measured at the end of the study. PI3K/Akt and ERK were evaluated by Western blot and qPCR assays. The results showed that OT plasma concentration was significantly increased in trained animals. The volume and weight of tumours were decreased significantly after both exercise training and OT administration. The expression of genes involved in tumour cell proliferation, such as PI3KR2, Akt and mTOR, was notably lower in the exercise-trained and OT-treated groups. Furthermore, the expression of genes involved in cell apoptosis, such as caspase-3 and Bax, was significantly increased in the tumour tissues. In addition, Western blot results showed that phosphorylated Akt and ERK were significantly decreased in the exercise training and OT groups compared with the tumour group. Interestingly, atosiban reversed these effects. These results indicated that interval exercise training, acting via OT secretion, may reduce PI3K/Akt and ERK axis activities, and consequently, decrease tumour volume and weight in a mouse model of breast cancer.

Wnt5A regulates the expression of ROR2 tyrosine kinase receptor in ovarian cancer cells.

Wnt5A and receptor tyrosine kinase-like orphan receptor 2 (ROR2) proteins both regulate developmental processes, cell movement, and cell polarity. The purpose of this study was to evaluate a possible regulatory role of Wnt5A on ROR2 expression in human ovarian cancer cell lines. Moreover, the expression of Wnt5A and ROR2 mRNA and protein levels were assessed in human epithelial serous ovarian cancer (HSOC) specimens. ROR2 was strongly decreased in cells treated with siRNA against Wnt5A compared with scramble-treated or lipofectamine-treated cells (P < 0.001). There was 34% decreased cell invasion (P < 0.01) in Wnt5A knock-down cells compared with lipofectamine-treated and scramble-treated cells; however, cell invasion remained unchanged upon addition of anti-ROR2 antibody to the culture media of these cells. In contrast, addition of anti-ROR2 antibody to the culture media for lipofectamine-treated and scramble-treated cells led to 32% decreased cell invasion (P < 0.01). Normal ovarian specimens were negative, and variable immunostaining was observed in HSOC for Wnt5A and ROR2 immunostaining. Furthermore, there was a positive correlation between Wnt5A and ROR2 expression in high-grade SOC samples at the mRNA level (P < 0.05; r = 0.38). This is the first report to show the regulatory role of Wnt5A on ROR2 expression in ovarian cancer.