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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.

SUBMITTER: Barbero S 

PROVIDER: S-EPMC2684981 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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

Barbero Simone S   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  

Cancer research 20090421 9


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 interac  ...[more]

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