Inhibition Of Breast Cancer By Blocking The Wnt/?-catenin Signaling Pathway

Wnt signaling pathway plays an important role in embryonic development and maintenance of tissue homeostasis.In the presence of Wnt stimulation,?-catenin is able to enter the nucleus and bind to the TCF/LEF transcription factor,which is involved in the transcriptional regulation of the target gene of Wnt signaling pathway.In contrary,CK1 and GSK3? that existed in the degradation complex can sequentially phosphorylate ?-catenin in the absence of Wnt protein,which makes ?-catenin degradation through the ubiquitin-proteasome pathway.Since the abnormal activation of Wnt signaling pathway plays a key role in the occurrence,development and metastasis of various tumors,it is of great significance to develop anticancer drugs against the Wnt signaling pathway.Prodigiosin(PG)is a secondary metabolite of bacteria,which belongs to a class of compounds characterized by three pyrrole ring structure.PG plays a good role in anti bacteria,fungi,protozoa,malaria and cancer.Studies have shown that PG has an anticancer effect in breast cancer with multidrug resistance or whose apoptosis pathway failed to function.However,its specific mechanism is not yet clear.In this study,we identified PG as a potent inhibitor of the Wnt signaling pathway through the high-throughput screening assay.Our results demonstrated that PG could specifically inhibit the Wnt signaling pathway by using a SuperTopFlash luciferase reporter system.We further found that PG may target upstream of ?-catenin complex,and PG is not an inhibitor of Porcupine.Moreover,we showed that PG can inhibit the phosphorylation of LRP6 and DVL2,and increase the GSK3? activity,resulting in suppressing ?-catenin–stimulated Wnt target gene expression.PG exerts inhibitory effects on growth,migration and invasion of breast cancer cells in vitro.In MDA-MB-231 breast cancer xenografts,administration of PG slowed tumor progression through blocking Wnt/?-catenin signaling.Through its ability to inhibit Wnt/?-catenin signaling,PG could have therapeutic activity in advanced breast cancers.