Mutations in p53, a critical tumour suppressor gene, occur in more than half of all cancers, frequently resulting in aggressive tumours and poor patient survival. Most of the chemotherapeutic drugs currently in clinical use work by causing apoptosis of cancer cells. However, cancer cells have the ability to evade apoptosis and acquire resistance to chemotherapeutic drugs. Recently, a new form of cell death called ferroptosis has been discovered which is distinct from apoptosis. It is characterised by accumulation of redox-active iron, glutathione depletion and the onset of lipid peroxidation. Great progress has been made in studying ferroptosis in various neurological and cardiovascular diseases however; potential application of ferroptosis in cancer is an area that requires further elucidation.
Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated as a tumour suppressor. Caspase-2 deficient (Casp2−/−) mice develop normally but show enhanced oxidative stress and impaired antioxidant response with ageing. 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 in combination with caspase-2 depletion, mutant-p53 cancer cells are exquisitely sensitive to cell death induced by various ferroptotic inducers. Furthermore, our data shows 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 antioxidant, glutathione. We further generated Casp2C320G mutant cells to demonstrate that caspase-2 catalytic activity is not essential for its function in limiting ferroptosis. Our results provide direct evidence that caspase-2 protects mutant-p53 cancer cells against ferroptotic cell death.