Commitment to apoptosis induced by tumour necrosis factor-alpha is dependent on caspase activity

Tumour Necrosis Factor alpha binding at the cell surface induces a complex series of signaling events culminating in the caspase cascade, which is central to apoptosis. However, recent work from several laboratories has questioned caspase involvement in commitment to cell death. We have therefore investigated the involvement of caspases in the crucial commitment stage of tumour necrosis factor-induced apoptosis in human T-leukaemic CEM-C7 cells and breast carcinoma MCF-7 cells, using both peptide-based and viral caspase inhibitors. Our observations converge on the conclusion that commitment to death in these systems is dependent on caspase activity, e.g. baculovirus p35 produces over 50-fold protection of colony-forming ability, the most stringent criterion of cell survival. These observations strongly support the view that the caspase family is of great biological and medical significance, since caspase dysfunction resulting in failure to commit to cell death after treatment with tumour necrosis factor or other stimuli may contribute to cancer development.