H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS

الملخص EN

Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells.

However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance.

This phenomenon can be attributed to the inherited high expression of antioxidant protein network.

H-Ferritin is an important member of the antioxidant system due to its ability to store iron in a nontoxic form.

Altered expression of H-Ferritin has been described in ovarian cancers; however, its functional role in cisplatin-based chemoresistance of this cancer type has never been explored.

Here, we investigated whether the modulation of H-Ferritin might affect cisplatin-induced cytotoxicity in ovarian cancer cells.

First, we characterized OVCAR3 and OVCAR8 cells for their relative ROS and H-Ferritin baseline amounts.

OVCAR3 exhibited lower ROS levels compared to OVCAR8 and greater expression of H-Ferritin.

In addition, OVCAR3 showed pronounced growth potential and survival accompanied by the strong activation of pERK/pAKT and overexpression of c-Myc and cyclin E1.

When exposed to different concentrations of cisplatin, OVCAR3 were less sensitive than OVCAR8.

At the lowest concentration of cisplatin (6 μM), OVCAR8 underwent a consistent apoptosis along with a downregulation of H-Ferritin and a consistent increase of ROS levels; on the other hand, OVCAR3 cells were totally unresponsive, H-Ferritin was almost unaffected, and ROS amounts met a slight increase.

Thus, we assessed whether the modulation of H-Ferritin levels was able to affect the cisplatin-mediated cytotoxicity in both the cell lines.

H-Ferritin knockdown strengthened cisplatin-mediated ROS increase and significantly restored sensitivity to 6 μM cisplatin in resistant OVCAR3 cells.

Conversely, forced overexpression of H-Ferritin significantly suppressed the cisplatin-mediated elevation of intracellular ROS subsequently leading to a reduced responsiveness in OVCAR8 cells.

Overall, our findings suggest that H-Ferritin might be a key protein in cisplatin-based chemoresistance and that its inhibition may represent a potential approach for enhancing cisplatin sensitivity of resistant ovarian cancer cells.