title: Requirement of nuclear factor κB for Smac mimetic-mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis.
abstract: 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.
authors.affiliation: University Children's Hospital, Ulm University, Ulm, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Stadel
authors.forename: Silvia
authors.initials: S
authors.lastname: Cristofanon
authors.forename: Behnaz Ahangarian
authors.initials: BA
authors.lastname: Abhari
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D051379:Mice; D024101:Mitochondrial Proteins / Q000737:chemistry*; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D020169:Caspases; D000093542:Gemcitabine