The Regulatory Effects And Underlying Mechanisms Of Sphingomyelin Metabolism On Abiraterone Resistance In Prostate Cancer Cells

ObjectiveAbiraterone(Abi),a novel androgen synthesis inhibitor,has been widely used to treat the metastatic hormone-sensitive prostate cancer(mHSPC)as well as metastatic castration-resistant prostate cancer(mCRPC),and proven to significantly prolong the patient’s survival time.Nevertheless,the acquisition of resistance to abiraterone has been a huge obstacle in clinical practice.Recently,accumulating evidence indicated the important role of lipid metabolism in drug resistance in cancer.However,whether the lipid metabolism could regulate the abiraterone resistance of prostate cancer(PCa),and the underlying mechanisms remain unclear.MethodsThe abiraterone-resistant prostate cancer cell line was established by stepwise exposure for 6 months.The content of sphingomyelin(SM)and the expression of ELOVL Fatty Acid Elongase 1(ELOVL1)in prostate cancer cell lines were determined by lipidomics,Lysenin(LYS)labeling,RNA-sequencing(RNA-seq),quantitative Real-Time PCR(qRT-PCR),and western blot assays.Colony formation assay was performed,and subcutaneous xenografted tumor model was constructed to evaluate the resistance of PCa cells to abiraterone.Database mining,dual-luciferase reporter assay,chromatin immunoprecipitation(ChIP)assay,and correlation analysis were performed to uncover the interaction among ELOVL1,SM metabolism,FOS,miRNAs,and ULK1.ResultsIn this study,the effect of SM metabolism on abiraterone resistance was determined in PCa cells,that is,the aberrantly upregulated SM content could facilitate the cytoprotective autophagy-mediated abiraterone resistance.Mechanistically,the reduction of SM content could downregulate the expression of transcription factor FOS,and relieve its inhibitory effect on the transcription of MIR377 and MIR1297 genes.In turn,upregulated miRNAs suppress the expression of downstream target ULK1,thereby inhibiting the cytoprotective autophagy of PCa cells.Biologically,reducing the content of SM or silencing the expression of ELOVL1 could significantly reverse abiraterone resistance in PCa cells.ConclusionsThe present study uncovered the promoting effects of ELOVL1/SM metabolism/FOS/miRNAs/ULK1 axis on the cytoprotective autophagy and abiraterone resistance,suggesting that the very signaling pathway may serve as a potential therapeutic target in abiraterone-resistant PCa patients.