Fig. 7

Sequence of molecular events leading to anti-proliferative and pro-apoptotic effects of KC-53 in leukemic cells. KC-53 stimulates TNFR1 and inhibits TRAF2 phosphorylation. RIP1 dissociates from TRAF2 and binds to the FADD/pro-caspase 8 complex. This leads to the activation of the procaspase-8 which in turns cleaves and inactivates RIP1. Caspase-8 triggers Bid cleavage, activation of effectors Caspases, −3 and −7 and inactivation of PARP1 promoting cell apoptosis. tBid leads to Caspase-9 activation and AIF release and translocation to the nucleus. The absence of RIP1 from TRADD/TRAF2 complex diminishes the phosphorylation of IκΒα by downstream kinases. As a result, IκΒα is not phosphorylated and fails to be ubiquitinated and degraded by proteasome. Subsequently, NF-κB remains in complex with IκΒα, fails to translocate to the nucleus and cell survival signaling is hindered. P phosphorylation, ub ubiquitination