The effect of iron on the expression levels of calcium related gene in cisplatin resistant epithelial ovarian cancer cells

Abstract

Aim: Anticancer drugs (chemotherapeutics) used in cancer treatment (chemotherapy) lead to drug resistance. This study was conducted to investigate the possible effect of iron on calcium homeostasis in epithelial ovarian cancer cells (MDAH-2774) and cisplatin-resistant cells of the same cell line (MDAH-2774/DDP). Methods: To develop MDAH-2774/DDP cells, MDAH-2774 (MDAH) cells were treated with cisplatin in dose increases of 5 μM between 0 μM and 70 μM. The effect of iron on the viability of MDAH and MDAH/DDP cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test at the end of 24 h incubation. Results: At increasing iron concentrations in MDAH and MDAH/DDP cells, the mRNA gene of fifteen genes [inositol 1,4,5-triphosphate receptor (IP3R)1/2/3, ryanodine receptor (RYR)1/2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)1/2/3, Na+/Ca2+ exchange (NCX)1/2/3, and plasma membrane Ca2+ ATPase (PMCA)1/2/3/4] associated with Ca2+ differences in expression were determined by quantitative reverse transcription-polymerase chain reaction. Changes in IP3R2, RYR1, SERCA2, NCX3, PMCA1, and PMCA3 gene expressions were observed in iron treatment of MDAH/DDP cells, while changes were detected in iron treatment of MDAH cells in IP3R1/2/3, RYR1/2, SERCA1/2/3, NCX2/3, and PMCA1 expressions. Conclusions: This changes in the expression of calcium channels, pumps, and exchange proteins in the epithelial ovarian cancer cell line and in cisplatin-resistant epithelial ovarian cancer cells suggest that iron may have an important role in regulating calcium homeostasis. Due to differences in the expression of genes that play of an important role in the regulation of calcium homeostasis in the effect of iron, drug resistance can be prevented by introducing a new perspective on the use of inhibitors and activators of these genes and thus cytostatic treatment strategies.

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

“…By comparison, IP3R2 has received less attention. Nonetheless, increased expression of the IP3R2 gene was observed in iron-treated epithelial OC cells and cisplatin-resistant cells of the same cell line, indicating its probable role in the development and progression of OC (110).…”

“…Furthermore, RyRs have been reported to regulate the activation of the unfolded protein response in OC cells and in turn their sensitivity to paclitaxel and adriamycin (116). A previous study found that both epithelial OC cells (MDAH-2774) and cisplatin-resistant OC cells of the same cell line (MDAH-2774/DDP) showed increased RyR1 gene expression after iron treatment, while only EOC cells (MDAH-2774) showed decreased RyR2 mRNA levels (110). This suggests that RyRs can affect the progression of OC by regulating Ca 2+ levels in OC cells through multiple mechanisms (Table II).…”

“…Ovarian granulosa cells rely on PMCA to regulate their [Ca 2+ ]i concentrations in response to basic fibroblast growth factor (bFGF), which suggests that bFGF regulates PMCA as part of an anti-apoptotic mechanism in ovarian granulosa cells (123,124). Iron treatment was found to upregulate the mRNA expression of both PMCA1 and PMCA3 in cisplatin-resistant epithelial OC cells, suggesting that PMCA is an independent pathway of drug resistance in OC cells (110). Additionally, the mRNA expression profiles of Ca 2+ homeostasis-associated genes (SERCA1/2/3, PMCA1/2/3/4) were decreased in a cisplatin-resistant cell line compared with those in their parental cell lines (Table II) (125).…”