Anti-cancer Mechanism Of GJ-51805 By Regulating RAR?

In China,the incidence of HCC ranks fourth in all malignancies,and the mortality is the second highest.Therefore,the prevention and treatment of liver cancer is particularly important.The retinoic acid receptor gama(RARy),a member of the nuclear receptor superfamily,plays an essential role in mediating biological processes such as cell proliferation,cell differentiation,cell cycle and apoptosis.RARy is an oncogenic protein in HCC,and oncogenic e(?)ect of RAR? is not due to its transcriptional regulation but lies in its non-genomic regulation.Targeting to this non-genomic signaling is expected to be a promising strategy to develop novel therapies.Through MTT,flowcytometry,colony formation,cell scratches,and immunofluorescence,we found that aza-steroid compounds,GJ-51802 and GJ-51805,have good anti-tumor effects.GJ-51802 and GJ-51805 can inhibit the proliferation of HCC:the IC50 of GJ-51802 and GJ-51805 is 7.5 ?M and 2.5 ?M respectively.GJ-51802 and GJ-51805 can inhibit the migration of HCC and down-regulate the expression level of MMP2.Both compounds cause early apoptosis and late apoptosis to some degree:induction of PARP cleavage,activation of Bax pro-apoptotic proteins.In addition,GJ-51802 and GJ-51805 arrest cell cycle in G2/M phase and down-regulate CDK1 expression.It may be related to highly expressed RARy in liver cancer.We found that GJ-51802 and GJ-51805 can down-regulate RARy in a dose-and time-dependent manner.Through reporter genes and proteolytic strategies,RARy may be a potential target of GJ-51805.GJ-51805 can disrupt the interaction between RARy and CDK1 through CO-IP.The co-localization of RARy and CDK1 is mainly in the nuclear.Therefore,we screened and obtained an aza-steroid compound GJ-51805,which can inhibit the cell cycle in G2/M by regulating RARy and disrupting the interaction between RARy and CDK1.This may be the anti-tumor mechanism of GJ-51805.