Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis.
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.
Barbero
Simone
S
Department of Pathology, Moores UCSD Cancer Center, University of California-San Diego, San Diego, California 92093, USA.
Mielgo
Ainhoa
A
Torres
Vicente
V
Teitz
Tal
T
Shields
David J
DJ
Mikolon
David
D
Bogyo
Matthew
M
Barilà
Daniela
D
Lahti
Jill M
JM
Schlaepfer
David
D
Stupack
Dwayne G
DG
D056769:Alstrom Syndrome; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016608:Talin / Q000378:metabolism
D002135:Calcium-Binding Proteins; D016608:Talin; C033668:calpastatin; D051416:Focal Adhesion Protein-Tyrosine Kinases; C505530:CASP8 protein, human; D002154:Calpain; D053181:Caspase 8; C569870:CAPN2 protein, human