Sensitivity of triple negative breast cancer cells to ATM-dependent ferroptosis induced by sodium selenite

Abstract

Targeting ferroptosis, a type of cell death elicited by Fe²⁺ and lipid reactive oxygen species (L-ROS), provides a novel strategy for cancer therapy. Selenium has the potential to treat cancers by acting as a pro-oxidative agent, thus leading to cancer cell death. Here, we found that the triple negative breast cancer (TNBC) MDA-MB-231 cells were more sensitive to ferroptosis induced by sodium selenite (Na₂SeO₃) than that of non-TNBC MCF-7 cells. Na₂SeO₃ significantly elevated the level of L-ROS, MDA and Fe²⁺, decreased the content of GSH and the enzyme activity of GPx, disrupted the expression of ferroptosis related proteins such as GPx4 and FTH1, as well as compromised mitochondrial morphology in MDA-MB-231 cells. Moreover, ATM was activated by Na₂SeO₃ in MDA-MB-231 cells. Notably, Na₂SeO₃-induced ferroptosis was inhibited by ATM kinase inhibitor KU55933 or siATM, suggesting that Na₂SeO₃-induced ferroptosis was mediated by ATM protein in MDA-MB-231 cells. Our findings suggest a therapeutic strategy by ferroptosis against TNBC and deepened our understanding of ATM function.

Keywords: ATM; Breast cancer; Cell death; Ferroptosis; Selenium.