TY  - JOUR
A1  - Laukens, Bram
A1  - Jennewein, Claudia
A1  - Schenk, Barbara
A1  - Vanlangenakker, Nele
A1  - Schier, Alexander
A1  - Cristofanon, Silvia
A1  - Zobel, Kerry
A1  - Deshayes, Kurt
A1  - Vucic, Domagoj
A1  - Jeremias, Irmela
A1  - Bertrand, Mathieu J. M.
A1  - Vandenabeele, Peter
A1  - Fulda, Simone
T1  - Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis
T2  - Neoplasia
N2  - Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54327
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-543274
SN  - 1476-5586
VL  - 13
IS  - 10
SP  - 971
EP  - 979
PB  - Elsevier
CY  - Amsterdam [u.a.]
ER  -