The Mechanism On The Regulation Of Jacaranone In CIAP2-mediated TNFα Survival And Death Conversion

Apoptosis inhibitory protein I/APs regulate a variety of biological processes.cIAPs are abnormally elevated in most human malignancies,and their overexpression is associated with tumor growth,poor prognosis and efficacy.cLAPs are involved in the regulation of cell fate.TNFa binds TNFRI to induce TRADD,TRAF2,TRAF5,cIAPl,clIAP2 and protein kinase RIP1 to form complex I.cIAPs mediate the ubiquitination of complex I components,such as RIPl,which induces recruitment of IKK complexes.IKKβ phosphorylates the NF-kB inhibitor to target ubiquitination-dependent proteasome degradation,thereby transporting NF-kB to the nucleus-initiating target gene expression.In the absence of cIAPs,RIP1 dissociates from the membrane-bound complex I and forms complex II with FADD,caspase 8,leading to activation of caspase 8 and induction of apoptosis.Thus,regulation of downstream signaling pathways through cIAPs is an effective target for the development of antineoplastic drugs.Jacaranone is a kind of natural compounds,exists in a variety of plants,with cytotoxicity and anti-tumor activity.In this study,it is found that Jacaranone could inhibit TNFa-induced activation of NF-kB,and under the stimulation of TNFa,Jacaranone could induce caspase 8 and PARP cleavage and enhance TNFa-induced apoptosis.The study of the mechanism of Jacaranone showed that Jacaranone could specifically ubiquitin cIAP2 and induce cIAP2 degradation to reduce the expression level of cIAP2 in tumor cells.The decrease of cIAP2 inhibits the formation of complex II and inhibits NF-kB signaling pathway.Down-regulating cIAP2 could also increase the formation of complex II to induced tumor cell apoptosis.This study uncovered the molecular mechanism of the apoptosis induced by Jacaranone,and provided a theoretical basis for the study of the anti-tumor activity of these compounds,which is of great significance for further development of potential anti-tumor drugs.