Nitrostyrene Derivatives Bind To RXRα And Inhibit TRXRα-Dependent TNFα/NFκB Signaling Pathway

Retinoid X receptor-α(RXRα).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 RXRα are highly related to tumor development.N-terminal truncated RXRα(tRXRα)has been revealed to promote tumor growth by enhancing TNFα-stimulated PI3K/AKT activation through its interaction with p85α,a regulatory subunit of PI3K.However,whether tRXRα is involved in regulating other signaling pathway remains elusive.The activity of RXRαis tightly regulated by its ligands.Thus,the discovery of novel ligands of RXRα is critical to understand its physiological and pathological functions.In this study,we show that tRXRα up-regulated TNFα/NFKB signal activity by interacting with TRAF2,a crucial signal transducer in TNFα/TNFR1/NFκB pathway.In an effort to identify novel ligands of RXRα.we found that nitrostyrene derivatives(Z-10 and Z-12)bound to RXRα in a unique manner,which resulted in a distinct RXRα conformational change and potent activation of RXRα transcriptional activity.Different from classic natural and synthetic RXRα ligands with a carboxyl group,Z serial compounds possess a nitro group,which was required for Z compounds binding to RXRα.Importantly.Z-10 and Z-12 were able to suppress TNFα-induced IκBαdegradation and NFκB transcriptional activity in a tRXRα dependent manner,which might be due to their inhibition of TRAF2 and tRXRa interaction.Furthermore,we revealed that tRXRα-dependant inhibition of TNFα/NFκB survival signaling pathway by Z compounds led to cancer cell apoptosis in vivo and in vitro via induction of extrinsic apoptotic pathway of TNFα.Together,our studies first identified the nitro-ligands of RXRα.We also revealed an unidentified tRXRα action of promoting tumor growth via enhancing TNFα/NFκB survival pathway,showing a new mode of TNFα/NFκB signaling regulation.Our studies also uncovered the action and mechanism of the synergistic inhibition of tumor growth by TNFα and Z compounds combination,implying a new lead and strategy for tRXRa-related cancer treatment.