Momordin Ic,A New Natural SENP1 Inhibitor,Inhibits Proliferation Of Prostate Cancer Cells

Purpose:It has been found that SENP1 is highly expressed in prostate cancer,and closely related with its occurrence,development and metastasis,so it is regarded as the potential target for prostate cancer treatment.We carried out this research to search for a new natural SENP1 inhibitor,then investigate its potential application in the treatment of prostate cancer and the corresponding mechanisms.Methods:We screened a new SENP1 inhibitor from natural pentacyclic triterpenoids by an in vitro deSUMOylation assay,and demonstrated its direct interaction with SENP1 by the cellular thermal shift assay(CETSA)and drug affinity responsive target stability(DARTS).Next,we applied this compound to prostate cancer cells,then explored SENP1 and SUMOylated protein expression by western blot,cell proliferation by CCK8 assay,cell cycle and apoptosis by flow cytometry.Furthermore,we established SENP1 stably overexpressed PCFlag-SENP1 cell lines and SENP1 stably knocked down PC3shSENP1 cell lines to verify whether this compound suppress the growth of prostate cancer by targeting SENP1.Finally,through the xenografted PC3 tumor mice model,we validated its effect on transplanted tumor growth in vivo.Results:Firstly,we showed that momordin Ic(Me),a natural pentacyclic triterpenoid,could inhibit the activity of SENP1 in a dose-dependent manner in vitro,as reflected by the inhibition of SENPIC-induced cleavage of SUM02-ARanGAPl.Then,by CETSA and DARTS,we further demonstrated that Me could change the thermal stability of SENP1 and reduce the degradation of protease to SENP1,indicating the direct engagement of Me with SENP1 in PC3 cells.Next,we found Me could increase the SUMOylated protein and reduce SENP1 expression in PC3 cells,meanwhile inhibit cell proliferation,induce G2/M arrest and increase cell apoptosis,while overexpression of SENP1 could partially reverse Mc-induced suppression on PC3 cells.Finally,by xenografted PC3 tumor mice model,we demonstrated that Me could suppress the tumor growth and increase cell apoptosis in vivo.Conclusion:We demonstrated that Me was a novel SENP1 inhibitor with potential therapeutic value for prostate cancer.Our findings also suggested that pentacyclic triterpenoids may serve as novel scaffolds for developing new SENP1 inhibitors.Objective: To observe the changes of lymphocyte subsets of peripheral blood in 2 common oral mucosa diseases,recurrent aphthous ulcer(RAU)and oral lichen planus(OLP),and to investigate their immunological pathogenesis.Methods: By flow cytometry,the lymphocyte subsets(total T cells,CD4+T cells,CD8+ T cells,CD4+/CD8+,NK cells and B cells)in the peripheral blood of patients with RAU(105 cases),OLP(70 cases)and healthy controls(65 cases).The difference was analyzed comparatively between the groups.Results: Compared with healthy controls,total T cells and CD8+ T cells in RAU groupincreased(P<0.05,P<0.01),but CD4+ T cells,CD4+/CD8+ and B cells decreased in RAU group(P<0.01,P<0.001,P<0.05).Inaddition,CD8+ T cells in OLP group were lower than those in control group(P<0.05).The total T cells and CD8+ T cells in RAU group were higher than those in OLP group(P<0.01,P<0.001),while CD4+ T cells,CD4+/CD8+ and NK cells in RAU group were significantly lower(P<0.01,P<0.001,P<0.05).Conclusions: Owing to the imbalanced lymphocyte subset percentages,the cellular immune function of patients with RAU or OLP is often found to be abnormal,but their immune states are not completely same.So,the application of selective immunologic intervention may be the promising therapeutic measure to those oral mucosa diseases.