The dependence receptor DCC defines a new mechanism for caspase activation

The DCC (Deleted in Colorectal Cancer) gene has been found to be deleted in more than 50% of primary colorectal cancers and in numerous other carcinomas, although the role of DCC as a tumor suppressor remains controversial. DCC is also a receptor for netrin-1, a lamininrelated molecule involved in axon guidance. Recently, we reported that DCC is actually a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand, but inhibiting apoptosis in the presence of ligand. Here, we show that DCC drives apoptosis through a mechanism requiring caspase-9 activation. Unexpectedly, if DCC kills through caspase-9, it does not go through the classic ‘mitochondria pathway’ since Bcl-2 and an inhibitor of cytochrome c release, cyclosporin A, are unable to block CCC-induced ceil death. Of interest, DCC intera& with both caspase3 and caspase-9 suggesting that DCC could play the role of an initiator complex for caspase activation. Moreover, in vitro translated DCC drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c. Hence, DCC defines the first pathway for cytochrome c-independent-and thus mitochondria-independentactivation of caspase-9.