The Small Molecules Targeted For Protein FKBP51 Inhibit The Androgen Receptorsignaling Pathway In Prostate Cancer

The prostate cancer,one of the most malignant tumors,is can be cured in early stage but it need more comprehensive treatments for pateints in advanced stage.Anti-androgenagent compete with androgen to combine into active sites of androgen receptor,which can decrease the androgen receptor signaling pathway and inhibit the growth of prostate cancer cells.However,the outcome of these antiandrogen drugs is satisfied in clinical application.As the developemt of structural biology,targeted for some proteins as the drug design are applicated in cancer therapy and more and more attention are paid on the structure of vital protein invoveled in tumor.The protein FKBP51,a positive regulator of AR,can contribute to prostate cancer.We screened small molecular inhibitors of FKBP51 by vitual screening methods and examed the effect on the growth of prostate cancer cells.Several samll compounds show the strong ability of inbiting the cell growth.Meanwhile,we studied the compound p-nitrophenol,which shows the anti-androgenic activity.It can easily become anthro-pogenic pollutants and pose a threat to the environment and human health.Previous work indicates that the anti-androgenic mechanism of p-nitrophenol is complex and may involve several components in the AR signaling pathway,but the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear.Here,we characterized p-nitrophenol binds to the FK1 domain of an AR positive regulator FKBP51 with micromolar affinity and structural analysis of FK1 domain in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic FK1 pocket that is vital for AR activity enhancement.Molecular dynamics simulation indicated that p-nitrophenol is stably bound to the FK1 pocket and the hotspot residues that involved p-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site.Furthermore,we showed that p-nitrophenol inhibits the androgen-dependent growth of human prostate cancer cells,possibly through down-regulating the expression levels of AR activated downstream genes.It is well known that rapaycin is an inhitor of FKBP51,whose main signaling pathway is mTOR in human and few reports on the influence of AR signaling pathway.Here,we studied the role of rapamycin inAR signaling pathway and how it interact with FKBP51.The results show that rapmycin can bind FKBP51 and occupy the FK1 pocket.Furthermore,it inhibits the growth of prostate cancer cells and dwon-regulates the mRNA expression level of downstream gene,resulting in the decrement expression of PSA protein.Taken together,our data suggests that p-nitrophenol and suppresse the AR signaling pathway at least in part by blocking the interaction between AR and its positive regulator FKBP51.Vitual screening molecularsinhibit prostate cancer cellsproliferation and its mechanism to be clarified Rapamycin inhibits the prostate cancer cell proliferation and downregulate the AR signaling,which may be imediated by FKBP51.We may believe that our findings could provide new guidelines for assessing the potential health effects of p-nitrophenol.