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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3755-3763
Number of pages9
JournalCancer Research
Volume69
Issue number9
DOIs
Publication statusPublished - May 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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