Inhibiting ?-Catenin by ?-Carboline-Type MDM2 Inhibitor for Pancreatic Cancer Therapy.

ABSTRACT: The ?-catenin and MDM2 oncoproteins are overexpressed and constitutively activated in human pancreatic cancer and contribute to its initiation, progression, and metastasis. The Wnt/?-catenin signaling pathway strongly interacts with the MDM2-p53 signaling pathway, accelerating the tumorigenesis and its development. Therefore, therapies inhibiting both ?-catenin and MDM2 are suggested to be ideal treatments for patients with advanced pancreatic cancer. We have recently identified a novel class of ?-carboline compounds as the specific and potent MDM2 inhibitors, including a lead compound SP141. In the present study, we utilized SP141 as an exemplary ?-carboline compound to characterize ?-catenin as a molecular target of the ?-carboline compounds and to demonstrate an important role of ?-catenin in the anticancer activity of ?-carboline. We found that the silencing of either ?-catenin or MDM2 largely reduced the anticancer activity of SP141 while the double silencing of both genes almost completely blocked SP141's activity. SP141 directly bound to ?-catenin and inhibited its expression and activity in pancreatic cancer cells in vitro and in vivo. The inhibitory effects of SP141 on ?-catenin were mediated by the ubiquitin-proteasome system in an MDM2-independent manner. In conclusion, these results suggest that SP141 exerts its anticancer activity by dually inhibiting ?-catenin and MDM2. We envision that ?-carboline derivatives can be developed as promising dual inhibitors of ?-catenin and MDM2 for the treatment of advanced pancreatic cancer.

SUBMITTER: Qin JJ 

PROVIDER: S-EPMC5776119 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature