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 language | English |
|---|---|
| Pages (from-to) | 3755-3763 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 69 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - May 1 2009 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis. / Barbero, Simone; Mielgo, Ainhoa; Torres, Vicente; Teitz, Tal; Shields, David J.; Mikolon, David; Bogyo, Matthew; Barilà, Daniela; Lahti, Jill M.; Schlaepfer, David; Stupack, Dwayne G.
In: Cancer Research, Vol. 69, No. 9, 01.05.2009, p. 3755-3763.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis
AU - Barbero, Simone
AU - Mielgo, Ainhoa
AU - Torres, Vicente
AU - Teitz, Tal
AU - Shields, David J.
AU - Mikolon, David
AU - Bogyo, Matthew
AU - Barilà, Daniela
AU - Lahti, Jill M.
AU - Schlaepfer, David
AU - Stupack, Dwayne G.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=65949097277&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65949097277&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-3937
DO - 10.1158/0008-5472.CAN-08-3937
M3 - Article
C2 - 19383910
AN - SCOPUS:65949097277
VL - 69
SP - 3755
EP - 3763
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 9
ER -