Inhibition of BMPR2 ubiquitination-dependent degradation suppresses bladder cancer cell growth via downregulating Smurf1 expression with 8003-1841

Background There is still a lack of effective treatment options for advanced bladder cancer (BC) in clinical practice. Smurf1 is an E3 ubiquitin ligase that enhances cancer cell growth and drug resistance through facilitating the ubiquitination and degradation of tumor suppressor proteins. However, there are no Smurf1 inhibitors approved for clinical use in cancer treatment at present. Similarly, there are currently no studies to confirm whether Smurf1 can be an effective therapeutic target for BC. Methods The biological effects of Smurf1 in BC were evaluated using MTT assay and colony formation assay. The mechanism by which Smurf1 promotes BC cell proliferation was investigated using Western blotting and Immunofluorescence. The Inhibitor of Smurf1 were screened using molecular docking. The changes of bladder cancer cells growth in vivo after Smurf1 inhibitors treatment were observed using a tumor xenograft model. The safety and mechanism of action of Smurf1 inhibitors in vivo were assessed using immunohistochemistry (IHC). Results In this study, our results revealed Smurf1 is high expressed in BC tissues, and the correlation between Smurf1 expression and poor prognosis in BC patients was evident. A set of in vitro and in vivo assays confirmed the role of Smurf1 in enhancing the proliferation of BC cells. Mechanistic studies revealed that Smurf1 promotes tumor progression by binding to BMPR2, facilitating BMPR2 ubiquitination and degradation in proteasome. Therefore, we further screened for effective inhibitors of Smurf1 from a ChemDiv database of 1,535,478 compounds in an attempt to explore new targeted drugs for BC. The results identified 8003 − 1841 as the strongest binder to Smurf1, which inhibited BC cell proliferation in vitro and in vivo by stabilizing the expression of BMPR2 through downregulation of Smurf1. Conclusion We have discovered a specific inhibitor, 8003 − 1841, that targets Smurf1 and effectively downregulates its expression. This inhibition of Smurf1 leads to the suppression of BC cell proliferation both in in vitro and in in vivo. Thus, our findings suggest that targeting Smurf1 could be a promising therapeutic approach for BC treatment. The inhibitor 8003 − 1841 shows potential as a treatment option for BC patients.