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

Departments of ¹Pathology and ²Reproductive Medicine and Moores UCSD Cancer Center, University of California-San Diego, San Diego, California; ³Departments of Genetics and Tumor Cell Biology, St. Jude Children's Hospital, Memphis, Tennessee; ⁴Department of Pathology, Stanford University School of Medicine, Stanford, California; and ⁵Department 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

^* To whom correspondence should be addressed. E-mail: dstupack{at}ucsd.edu.

	Abstract

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]

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