Members of the caspase family are essential for all apoptotic programs. We studied mouse embryonic fibroblasts (MEFs) deficient in caspases 3 and 7 (DKO) and caspase 9 (9KO) to determine the role of these proteases in endoplasmic reticulum (ER) stress-induced apoptosis, a potentially useful therapeutic target in cancer cells. Both DKO and 9KO MEFs were resistant to cytotoxicity induced via ER stress and failed to exhibit apoptotic morphology. Specifically, apoptosis induced by increased intracellular calcium was shown to depend only on caspases 3 and 9, while apoptosis induced by disruption of ER function depended additionally on caspase 7. Further, DKO and 9KO MEFs exhibited decreased loss of mitochondrial membrane potential, and these observations correlated with altered caspase 9 processing, increased induction of procaspase 11, and decreased processing of caspase 12 in DKO cells. Furthermore, disruption of ER function was sufficient to induce accumulation of cleaved caspase 3 and 7 in the ER compartment, providing a potential mechanism for caspase 12 processing. Thus, while caspases 3 and 9 are required for the ER stress apoptotic program, caspase 12 functions as an amplifier. This study irrefutably establishes a key role for the intrinsic pathway in ER stress-induced apoptosis and opens new possibilities for therapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA