Karolina Kowalska

AOH induces oxidative stress and DNA damage in ovarian cancer cells via modulation of GPER1 and HIF1α/PI3K/CLDNs signaling pathway

Claudins (CLDNs) are small proteins that form tight junctions (TJs) in cells and play a key role in various biological processes in cells. Previous results have shown that CLDNs expression can be regulated by hormones and, therefore, can also be regulated by compounds that mimic their action. Such compounds belong to a large group called endocrine-disrupting chemicals (EDCs). Alternariol (AOH), an emerging mycotoxin, contaminates various food products. AOH is reported to be genotoxic and to induce oxidative stress. Previous results showed that AOH is also estrogenic and acts as an androgen receptor (AR) agonist, suggesting that it might act as one of the EDCs, however, its detailed molecular mechanism has not been fully elucidated yet. In this study, we decided to evaluate the interplay between AOH and G protein-coupled estrogen receptor 1 (GPER1) in hormone-dependent human ovarian cancer (OC) cells with a focus on the involvement of hypoxia-inducible factor 1-alpha/phosphoinositide 3-kinases/protein kinase B (HIF1α/PI3K/Akt) and claudins (CLDNs) signaling pathways in that effect. We observed that AOH induces oxidative stress and DNA damage in OC cells, and this effect is partially mediated by GPER1. We found that the GPER1 antagonist G15 partially mitigated AOH-induced ROS production and significantly reduced DNA damage, confirming the receptor's role in mediating these effects. Furthermore, we observed the involvement of HIF1α/PI3K/Akt and CLDNs pathways in AOH effect in OC cells. In conclusion, we postulate that AOH has pro-oxidative ability and that this effect is partially mediated by GPER1. Moreover, we postulated that HIF1α/PI3K/Akt and CLDNs participate in AOH action in OC cells, which in turn provides useful information for future toxicological research studies as a new molecular mechanism of AOH.

Methylsulfonylmethane sensitizes endometrial cancer cells to doxorubicin

Abstract Background Methylsulfonylmethane (MSM) is a commonly used diet supplement believed to decrease the inflammation in joints and fastens recovery in osteoarthritis, gastric mucosal injury, or obesity-related disorders. It was also suggested that MSM might play a beneficial role in cancer treatment. Purpose So far, the MSM might have a potentially beneficial effect in endometrial cancer (EC) treatment. Study design This study evaluated the effect and usefulness of MSM in combinatory therapy with known drug doxorubicin (DOX). Methods The effect of combinational treatment of MSM and DOX on the induction of apoptosis was evaluated in EC cell lines (ISHIKAWA, MFE-296, MFE-280). Results We observed that MSM itself induces apoptosis in EC cell lines, and pre-treatment with MSM for 24 h increases the sensitivity of EC cells to DOX-induced apoptosis and DNA damage and that effect might be regulated by p42/44 (Erk1/2) MAPK and Akt (protein kinase B). Conclusion These results for the first time show that MSM might act as a sensitizer of EC cells to known drugs, for which EC cells quickly acquire resistance.

The Influence of Angiotensin Peptides on Survival and Motility of Human High-Grade Serous Ovarian Cancer Cells in Serum Starvation Conditions

High-grade serous ovarian carcinoma (HGSOC) is the most frequent and malignant form of ovarian cancer. A local renin–angiotensin system (RAS) has been found in the ovary, and changes in selected components of this system were observed in pathological states and also in ovarian cancer. In the present study, we examined the effect of three peptides, Ang-(1-7), Ang-(1-9) and Ang-(3-7), on proliferation and motility of the OVPA8 cell line, a new well-defined and preclinical model of HGSOC. We confirmed the presence of mRNA for all angiotensin receptors in the tested cells. Furthermore, our findings indicate that all tested angiotensin peptides increased the metabolic serum in the medium by activation of cell defense mechanisms such as nuclear factor kappaB signaling pathway andapoptosis. Moreover, tested angiotensin peptides intensified serum starvation-induced cell cycle arrest at the G0/G1 phase. In the case of Ang-(3-7), a significant decrease in the number of Ki67 positive cells (Ki67+) and reduced percentage of activated ERK1/2 levels in ovarian cancer cells were additionally reported. The angiotensin-induced effect of the accumulation of cells in the G0/G1 phase was not observed in OVPA8 cells growing on the medium with 10% FBS. Moreover, in the case of Ang-(3-7), the tendency was quite the opposite. Ang-(1-7) but not Ang-(1-9) or Ang-(3-7) increased the mobility of reluctant-to-migrate OVAP8 cells cultured in the serum-free medium. In any cases, the changes in the expression of VIM and HIF1A gene, associated with epithelial–mesenchymal transition (EMT), were not observed. In conclusion, we speculate that the adaptation to starvation in nutrient-deprived tumors can be modulated by peptides from the renin–angiotensin system. The influence of angiotensin peptides on cancer cells is highly dependent on the availability of growth factors and nutrients.