Nitrostyrene Derivatives Bind To RXR? And Inhibit TRXR?-Dependent TNF?/NF?B Signaling Pathway

Retinoid X receptor-?(RXR?).a member of the nuclear receptor superfamily,plays a variety of roles in many biological processes.It is widely reported that dysfunction and abnormal expression of RXR? are highly related to tumor development.N-terminal truncated RXR?(tRXR?)has been revealed to promote tumor growth by enhancing TNF?-stimulated PI3K/AKT activation through its interaction with p85?,a regulatory subunit of PI3K.However,whether tRXR? is involved in regulating other signaling pathway remains elusive.The activity of RXR?is tightly regulated by its ligands.Thus,the discovery of novel ligands of RXR? is critical to understand its physiological and pathological functions.In this study,we show that tRXR? up-regulated TNF?/NFKB signal activity by interacting with TRAF2,a crucial signal transducer in TNF?/TNFR1/NF?B pathway.In an effort to identify novel ligands of RXR?.we found that nitrostyrene derivatives(Z-10 and Z-12)bound to RXR? in a unique manner,which resulted in a distinct RXR? conformational change and potent activation of RXR? transcriptional activity.Different from classic natural and synthetic RXR? ligands with a carboxyl group,Z serial compounds possess a nitro group,which was required for Z compounds binding to RXR?.Importantly.Z-10 and Z-12 were able to suppress TNF?-induced I?B?degradation and NF?B transcriptional activity in a tRXR? dependent manner,which might be due to their inhibition of TRAF2 and tRXRa interaction.Furthermore,we revealed that tRXR?-dependant inhibition of TNF?/NF?B survival signaling pathway by Z compounds led to cancer cell apoptosis in vivo and in vitro via induction of extrinsic apoptotic pathway of TNF?.Together,our studies first identified the nitro-ligands of RXR?.We also revealed an unidentified tRXR? action of promoting tumor growth via enhancing TNF?/NF?B survival pathway,showing a new mode of TNF?/NF?B signaling regulation.Our studies also uncovered the action and mechanism of the synergistic inhibition of tumor growth by TNF? and Z compounds combination,implying a new lead and strategy for tRXRa-related cancer treatment.