Ferroptosis is a recently coined non-apoptotic cell death characterised by accumulation of redox-active iron, glutathione depletion and the onset of lipid peroxidation. Functionally, ferroptosis is suppressed by lipophilic antioxidants and iron chelators. Accumulated evidence has shown that activation of ferroptosis contributes to anticancer treatment for several forms of human cancer. However, the exact function of ferroptosis in cancer still remains elusive. We have previously demonstrated that accumulation of mutant p53 protein enhances ferroptosis.
Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in the maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2−/−) mice develop normally but show premature ageing-related traits including enhanced oxidative stress and impaired antioxidant response. Therefore, we hypothesised that caspase-2 may play a role in ferroptosis. We investigated the effect of various ferroptosis inducing small molecules following caspase-2 depletion in isogenic p53-null/mutant-p53 cell line models. Our results demonstrate that acute silencing of caspase-2 dramatically enhanced ferroptotic cell death, particularly in mutant p53 cancer cells, which could be fully rescued by various inhibitors of ferroptosis. Furthermore, our data show that depletion of caspase-2 results in downregulation of SLC7A11 expression, a key component of the glutamate/cystine exchanger (system xCT) thereby impairing cystine uptake and lowering the endogenous stores of the major cellular anti-oxidant, glutathione. Thus, in combination with caspase-2 depletion, mutant p53 cancer cells are exquisitely sensitive to cell death induced by various ferroptotic inducers. Our results provide direct evidence that caspase-2 protects against ferroptotic cell death and further work is ongoing to characterize whether catalytic activity of caspase-2 is essential for its function in limiting ferroptosis. Ultimately, a more comprehensive understanding of the molecular mechanism underpinning ferroptosis could allow utilization of this cell death pathway as an anti-cancer strategy.