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