TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death.

摘要: Programmed necrosis is important in many (patho)physiological settings. For specific therapeutic intervention, however, a better knowledge required whether occurs through one single “core program” or several independent pathways. Previously, the poly(ADP-ribose) polymerase (PARP) pathway has been suggested as crucial element of tumor factor (TNF)-mediated necroptosis. Here, we show that TNF-induced necroptosis and PARP represent distinct routes to programmed necrosis. First, DNA-alkylating agents such 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) methyl methanesulfonate rapidly activate pathway, whereas this late secondary event Second, inhibition does not protect against necroptosis, e.g., PARP-1 inhibitor 3-AB prevented MNNG- but adenosine-5′-triposphate depletion, translocation apoptosis-inducing factor, Likewise, olaparib, more potent selective failed block identical knockdown/knockout PARP-1, pharmacologic genetic interference with c-Jun N-terminal kinases calpain/cathepsin proteases further components pathway. Third, interruption by ceramide generation, RIP1 RIP3 function radical scavenger butylated hydroxyanisole did prevent In summary, our results suggest currently established role needs be revised, consequences for design future strategies.