Caspase function in apoptosis and cancer cell death

Lien Ho, Loretta Dorstyn and Robyn Taylor

Caspases are cysteine proteases that act as executioners of apoptosis. Having cloned one of the first caspases (caspase-2) our laboratory has an ongoing program in understanding caspase biology, regulation and function. Our current focus is to delineate the in vivo function of caspase-2. Accumulated data support a critical function for caspase-2 as an initiator caspase which links death signals to mitochondrial outer membrane permeabilization (MOMP). We have found that while mouse embryonic fibroblasts (MEFs) from caspase-2 null mice are normally sensitive to a number of chemotherapeutic drugs, they show significant resistance to killing by drugs that are known to induce apoptosis by disrupting the cytoskeleton. Reduced caspase-2 expression is often associated with many cancers and low caspase-2 levels have been correlated with drug-resistance. Thus it is likely that caspase-2 is required for apoptosis under certain pathological conditions, such as cancer. We are addressing this issue by using caspase-2 knockout mice and mouse models of cancer.