Hypoxic conditions increases H2S-induced ER stress in A2870 cells

Abstract

Hypoxia - a state of lower oxygen demand-is responsible for a higher aggressiveness of tumors and therefore a worse prognosis. During hypoxia, several metabolic pathways are re-organized, e.g., energetic metabolism, modulation of pH, and calcium transport. Calcium is an important second messenger that regulates variety of processes in the cell. Thus, aim of this work was to compare H2S modulation of the intracellular calcium transport systems in hypoxia and in cells grown in standard culture conditions. For all experiments, we used ovarian cancer cell line (A2780). H2S is a novel gasotransmitter, known to be involved in a modulation of several calcium transport systems, thus resulting in altered calcium signaling. Two models of hypoxia were used in our study-chemical (induced by dimethyloxallyl glycine) and 2 % O2 hypoxia, both combined with a treatment using a slow H2S donor GYY4137. In hypoxia, we observed rapid changes in cytosolic and reticular calcium levels compared to cells grown in standard culture conditions, and these changes were even more exagerrated when combined with the GYY4137. Changes in a calcium homeostasis result from IP3 receptor´s up-regulation and down-regulation of the SERCA 2, which leads to a development of the endoplasmic reticulum stress. Based on our results, we propose a higher vulnerability of calcium transport systems to H2S regulation under hypoxia.

In vitro culture expansion impairs chondrogenic differentiation and the therapeutic effect of mesenchymal stem cells by regulating the unfolded protein response

“…Extensive increase or decrease in ER stress disrupts the balance of bone homeostasis and physiology [ 30 ]. BMSCs adapt themselves in a native hypoxic microenvironment in vivo [ 31 – 33 ], which always serves as an important stimulus of ER stress [ 34 ]. BMSCs had impaired chondrogenic potential after isolation and culture under normoxic conditions in vitro [ 35 , 36 ] , in accordance with the change in ER stress.…”

Calcium signals and potential therapy targets in ovarian cancer (Review)

“…Hypoxia has been shown to control the intensity of Ca 2+ signaling in cancer cells through IP3Rs (103). In addition, Lencesova et al (104) previously demonstrated that hydrogen sulfide causes ER stress and apoptosis under hypoxic conditions, suggesting that IP3Rs are closely associated with apoptosis in OC cells. Additionally, stable TAT-fused IP3R1-derived peptides can increase cisplatin-induced Ca 2+ flux from the ER into the cytosol and mitochondria, sensitizing OC cells to cisplatin by targeting the BH4 structural domain of Bcl-2 (Table II) (105,106).…”

The potential role of hydrogen sulfide in cancer cell apoptosis

“…Meanwhile, knockdown of CBS also significantly inhibites the growth of nude mouse tumor xenografts and enhances the inhibition of cisplatin. A team find that in ovarian cancer cell line A2780 cells, GYY4137 induces ER stress under hypoxic conditions, leading to apoptosis in a Ca 2+ -dependent manner [ 96 ]. Moreover, in ovarian cancer cell line A2780, GYY4137 induces intracellular acidification by uncoupling the highly expressed sodium-hydrogen exchanger 1 (NHE1) from sodium-calcium exchanger 1 (NCX1) [ 97 ].…”