Regulation of ferroptosis in KRas mutant cancer cells

Abstract

Ferroptosis is a non‐apoptotic, iron‐dependent form of cell death driven primarily by accumulation of iron‐dependent lipid ROS due to GSH depletion or inactivation of glutathione peroxidase 4 (GPX4). GPX4 is the initiator of ferroptosis within the cancer cell. Cancer cells exhibit an increased iron demand compared with normal cells, and thus the iron‐dependency of the cancer cells can be explored to make them more susceptible to iron‐dependent ferroptosis. However, the role of ferroptosis in tumorigenesis remains unclear. KRas mutations are frequently associated with treatment resistance, partly due to defective apoptotic signaling. To date, clinical trials to develop compounds that target mutant Ras proteins have been unsuccessful. Here we showed that erastin treatment, a ferroptosis inducer, reduced cell proliferation, which was correlated with an increase level of cleaved caspase 3 and PARP in KRas mutant lung cancer cells. Interestingly, mutant KRas inhibition by chemical compounds targeting KRas G12C or G12D, coupled with erastin treatment, significantly reduced cell proliferation and promoted cleavege of caspase 3 and PARP‐1. These results suggest that KRas activity may negatively regulate erastin‐induced ferroptosis. To further investigate the regulatory mechanism that mediates erastin‐induced ferroptosis, we determined GPX4 expression after treatment with a mutant KRas inhibitor and/or erastin. We found that GPX4 expression level was not significantly changed by the mutant KRas inhibitor, suggesting that KRas may be targeting GPX4 enzyme activity rather than its expression. Taken together, these results suggest that KRas may play an important role in regulating erastin‐induced ferroptosis.