Nuclear Receptor Nur77 Mediated Apoptotic Signaling Pathway And Regulation

Nur77(also named TR3、NR4A1、NAK-1、NGGI-B)is an orphan nuclear receptor,it is encoded by the early gene and involved in the multiple signaling pathways,including the cellular stress response.Nur77 is involved in the biological process including cell proliferation、differentiation、apoptosis、autophagy、migration、metabolism and inflammation.Cell growth factors and apoptosis-inducing factor significantly induce the expression of Nur77.Not only that,Nur77 interact with other protein to regulate the biological function.The other important is the non-genomic function of Nur77,many factors induce apoptosis by affecting the subcellular localization of Nur77.After all,Nur77 plays a wide variety of biological function by complex regulatory network.CD437 was developed as a RARγ-selective agonist,which has been demonstrated to effectively inhibit the growth of a variety of cancer cell lines.However,the involvement of RARγ in the apoptotic signaling of CD437 remains debate.We report here that a CD437 could effectively induce apoptosis of cancer cells through its activation of Jun N-terminal kinase(JNK).Apoptosis induction by CD437 in cancer cells was suppressed by chemical inhibitors of JNK.CD437 induces JNK-mediated apoptosis in a manner dependent on Nur77 expression.Further investigation showed that inhibition of the expression of RARy abated the death effect of CD437,and overexpression of RARy could enhance the apoptotic effect of CD437 due to stabilizing the expression of Nur77.Further research has shown that RARy antagonizes the degradation of Nur77 through inhibiting its ubiquitination and directly interacts with Nur77,which was enhanced by CD437.Molecular analysis demonstrated that even though CD437 induces Nur77 expression independent on JNK,the activation of JNK by CD437 is important for its induction of Nur77 nuclear export and mitochondrial localization,a known apoptotic event in cancer cells.Together,our results revealed a molecular mechanism for controlling the apoptotic effect of CD437,in that RARy signaling antagonizes the degradation of Nur77,favoring its stabilization to induce apoptosis triggered by CD437.Nur77 was considered as a pro-oncogenic factor,and it is overexpression in breast cancer,colon,pancreatic cancer and other tumors.Nevertheless,Nur77 has been shown to inhibit cell growth and induce apoptosis in multiple of cancer cell types.These findings suggest that Nur77 has both a tumor suppressive and pro-oncogenic effect in the development of cancer.Given that Nur77 is an excellent drug target,identification of its potential ligands will be of therapeutic significance.In this study,we screened a series of compounds to discover drug targeting Nur77.Interestingly,GH-10 and GC-12 has shown great impact on growth inhibition and cell cycle arrest in cancer cells.Furthermore,the two compounds showed great effect on induction of apoptosis,also greatly influenced the migration and invasion in MCF-7.Interestingly,GH-10 and GC-12 could inhibit the expression of Nur77 in dose dependent way and the apoptotic effect is dependent on the Nur77 expression.Further study of molecular mechanism,GH-10 and GC-12 induce Bax activation and apoptosis through inhibiting AKT activity.Therefore,our findings demonstrate that the compounds,GH-10 and GC-12 have great inhibition of proliferation,migration and invasion,also significantly induce apoptosis,cell cycle arrest and inactivate AKT pathway in MCF-7,suggesting GH-10 and GC-12 as a promising lead for breast cancer therapy.