TY  - JOUR
A1  - Stadel, Dominic
A1  - Cristofanon, Silvia
A1  - Abhari, Behnaz
A1  - Deshayes, Kurt
A1  - Zobel, Kerry
A1  - Vucic, Domagoj
A1  - Debatin, Klaus-Michael
A1  - Fulda, Simone
T1  - Requirement of nuclear factor κb for smac mimetic–mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis
T2  - Neoplasia
N2  - Defects in apoptosis contribute to treatment resistance and poor outcome of pancreatic cancer, calling for novel therapeutic strategies. Here, we provide the first evidence that nuclear factor (NF) κB is required for Smac mimetic– mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. The Smac mimetic BV6 cooperates with gemcitabine to reduce cell viability and to induce apoptosis. In addition, BV6 significantly enhances the cytotoxicity of several anticancer drugs against pancreatic carcinoma cells, including doxorubicin, cisplatin, and 5-fluorouracil. Molecular studies reveal that BV6 stimulates NF-κB activation, which is further increased in the presence of gemcitabine. Importantly, inhibition of NF-κB by overexpression of the dominant-negative IκBα superrepressor significantly decreases BV6- and gemcitabine-induced apoptosis, demonstrating that NF-κB exerts a proapoptotic function in this model of apoptosis. In support of this notion, inhibition of tumor necrosis factor α (TNFα) by the TNFα blocking antibody Enbrel reduces BV6- and gemcitabine-induced activation of caspase 8 and 3, loss of mitochondrial membrane potential, and apoptosis. By demonstrating that BV6 and gemcitabine trigger a NF-κB–dependent, TNFα-mediated loop to activate apoptosis signaling pathways and caspase-dependent apoptotic cell death, our findings have important implications for the development of Smac mimetic–based combination protocols in the treatment of pancreatic cancer.
Y1  - 2011
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54341
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-543414
SN  - 1476-5586
SN  - 1522-8002
N1  - Under a Creative Commons license
VL  - 13
IS  - 12
SP  - 1162
EP  - 1170
PB  - Stockton Press
CY  - Basingstoke
ER  -