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

ABSTRACT

The ß-catenin and MDM2 oncoproteins are overexpressed and constitutively activated in human pancreatic cancer and contribute to its initiation, progression, and metastasis. The Wnt/ß-catenin signaling pathway strongly interacts with the MDM2-p53 signaling pathway, accelerating the tumorigenesis and its development. Therefore, therapies inhibiting both ß-catenin and MDM2 are suggested to be ideal treatments for patients with advanced pancreatic cancer. We have recently identified a novel class of ß-carboline compounds as the specific and potent MDM2 inhibitors, including a lead compound SP141. In the present study, we utilized SP141 as an exemplary ß-carboline compound to characterize ß-catenin as a molecular target of the ß-carboline compounds and to demonstrate an important role of ß-catenin in the anticancer activity of ß-carboline. We found that the silencing of either ß-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 ß-catenin and inhibited its expression and activity in pancreatic cancer cells in vitro and in vivo. The inhibitory effects of SP141 on ß-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 ß-catenin and MDM2. We envision that ß-carboline derivatives can be developed as promising dual inhibitors of ß-catenin and MDM2 for the treatment of advanced pancreatic cancer.