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Caspase-8 Association with the Focal Adhesion Complex Promotes Tumor Cell Migration and Metastasis

Departments of ¹ Pathology and ² Reproductive Medicine and Moores UCSD Cancer Center, University of California-San Diego, San Diego, California; ³ Departments of Genetics and Tumor Cell Biology, St. Jude Children's Hospital, Memphis, Tennessee; ⁴ Department of Pathology, Stanford University School of Medicine, Stanford, California; and ⁵ Department of Biology, University of Rome Tor Vergata and Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione Santa Lucia, Rome, Italy

Requests for reprints: Dwayne G. Stupack, Department of Pathology, Moores UCSD Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093. Phone: 858-822-1150; Fax: 858-822-1975; E-mail: dstupack{at}ucsd.edu.

Key Words: Calpain 2 • Calpastatin • Focal Adhesion Kinase • Apoptosis • Neuroblastoma

Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote cell migration among nonapoptotic cells; here, we show that caspase-8 can promote metastasis when apoptosis is compromised. Migration is enhanced by caspase-8 recruitment to the cellular migration machinery following integrin ligation. Caspase-8 catalytic activity is not required for caspase-8–enhanced cell migration; rather, caspase-8 interacts with a multiprotein complex that can include focal adhesion kinase and calpain 2 (CPN2), enhancing cleavage of focal adhesion substrates and cell migration. Caspase-8 association with CPN2/calpastatin disrupts calpastatin-mediated inhibition of CPN2. In vivo, knockdown of either caspase-8 or CPN2 disrupts metastasis among apoptosis-resistant tumors. This unexpected molecular collaboration provides an explanation for the continued or elevated expression of caspase-8 observed in many tumors. [Cancer Res 2009;69(9):3755–63]

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