Caspase-8 Association with the Focal Adhesion Complex Promotes Tumor Cell Migration and Metastasis

被引:114
作者
Barbero, Simone [1 ]
Mielgo, Ainhoa [1 ]
Torres, Vicente [1 ]
Teitz, Tal [3 ,4 ]
Shields, David J. [1 ]
Mikolon, David [1 ]
Bogyo, Matthew [5 ]
Barila, Daniela [6 ,7 ]
Lahti, Jill M. [5 ]
Schlaepfer, David [2 ]
Stupack, Dwayne G. [1 ]
机构
[1] Univ Calif San Diego, Moores UCSD Canc Ctr, Dept Pathol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Moores UCSD Canc Ctr, Dept Reprod Med, La Jolla, CA 92093 USA
[3] St Jude Childrens Res Hosp, Dept Genet, Memphis, TN USA
[4] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN USA
[5] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA
[6] Univ Roma Tor Vergata, Dept Biol, Rome, Italy
[7] Fdn Santa Lucia, Ist Ricovero & Cura Carattere Sci, Lab Cell Signaling, Rome, Italy
关键词
INTEGRIN ACTIVATION; CHILDHOOD NEUROBLASTOMAS; C-FLIPL; CALPAIN; APOPTOSIS; GENE; PROTEASE; SRC; MOTILITY; CANCER;
D O I
10.1158/0008-5472.CAN-08-3937
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. [Cancer Res 2009;69(9):3755-63]
引用
收藏
页码:3755 / 3763
页数:9
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