Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis.

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.

• Authors: Simone Barbero, Ainhoa Mielgo, Vicente Torres, Tal Teitz, David J Shields, David Mikolon, Matthew Bogyo, Daniela Barilà, Jill M Lahti, David Schlaepfer, Dwayne G Stupack
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 9 Pg. 3755-63 (May 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19383910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Talin
• calpastatin
• Focal Adhesion Protein-Tyrosine Kinases
• CASP8 protein, human
• Calpain
• Caspase 8
• CAPN2 protein, human

Topics

• Alstrom Syndrome
• Animals
• Calcium-Binding Proteins (metabolism)
• Calpain (metabolism)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cell Movement (physiology)
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Focal Adhesions (metabolism)
• Humans
• Lung Neoplasms (enzymology, metabolism, pathology)
• Mice
• Mice, Transgenic
• Neoplasm Metastasis
• Neuroblastoma (enzymology, metabolism, pathology)
• Talin (metabolism)