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Caspase-3 is known as a cysteine protease that primarily executes the cell death program. However, some tumors express higher levels of caspase-3 in positive correlation with malignancy. Here, we showed that caspase-3 can promote tumor metastasis in a protease-independent mechanism. Ectopic expression of caspase-3 enhanced lung metastasis and cell motility of caspase-3 deficient MCF-7 cells. By contrast, caspase-3 siRNA reduced the invasiveness and metastasis ability of A549 cells that express high level of caspase-3. Moreover, caspase-3 induced ERK activation. Alteration of caspase-3 by introducing non-processable mutation at its cleavage site or treatment of caspase-3 inhibitor did not diminish the caspase-3-associated increases in ERK phosphorylation and cell migration. Confocal microscopy study showed that caspase-3 was not physically associated with ERK. Inhibiting ceramide formation by blockage of the ceramide synthase or acid sphingomyelinase activity resulted in significant reduction of ERK phosphorylation and cell migration. In summary, caspase-3 induces ERK activation through a ceramide-dependant, protease activity-independent mechanism, which represents a novel role of caspase-3 in tumor metastasis. © 2008 Wiley-Liss, Inc.