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

Abstract

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.

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

“…Thanks to the substantial advances in understanding the molecular basis of cancer initiation, progression, metastasis, and drug resistance, several promising molecular targets have been characterized for cancer drug discovery, including β-catenin ( Cui et al., 2018 ; Qi et al., 2020 ). Considering the critical role of β-catenin signaling in cancer development and progression, several targeting strategies have been developed to inhibit β-catenin, resulting in the identification of various types of β-catenin inhibitors ( Krishnamurthy and Kurzrock, 2018 ; Qin et al., 2018b ). Natural products and natural product-derived compounds remain an important source for the discovery and development of new anticancer drugs ( Qian et al., 2013 ; Qin et al., 2018a ; Davison and Brimble, 2019 ).…”

“…β-Catenin is overexpressed and constitutively activated in human cancer and contributes to cancer initiation, progression, metastasis, drug resistance, and immune evasion ( Pai et al., 2017 ; Cui et al., 2018 ). Targeting β-catenin signaling has been proposed as a promising strategy to develop effective anticancer agents ( Qin et al., 2018b ; Cheng et al., 2019 ). Recent advances in understanding the protein structures of β-catenin alone and complexed with its coactivators have promoted the design and development of specific small-molecule inhibitors ( Krishnamurthy and Kurzrock, 2018 ; Zhang X. et al., 2020 ).…”

Antimicrobial Peptide Reverses ABCB1-Mediated Chemotherapeutic Drug Resistance

“…A molecular docking study was performed by Sybyl/Surflex-dock based on crystal structures of ABCB1 ( Qin et al., 2017 ; Qin et al., 2018 ). Peptide HX-12C was depicted by Sybyl/Sketch module (Tripos Inc.), optimized by applying Powell’s method with Tripos force field with convergence criterion set at 0.05 kcal/(Å mol), and assigned by the Gasteiger-Hückel method.…”

Terphenyllin Suppresses Orthotopic Pancreatic Tumor Growth and Prevents Metastasis in Mice

“…Panc1 and HPAC cells were seeded in 6-cm dishes (3-5×10 5 cells/well) overnight and exposed to terphenyllin (20, 50, or 200 mM) or DMSO for 24 h. The treated cells were then lysed with RIPA buffer (Absin Bioscience Inc, Shanghai, China) containing protease inhibitors (Solarbio Science & Technology Co., Ltd., Beijing, China) and phosphatase inhibitors (Roche, Switzerland). The cell lysates were centrifuged and the supernatants were collected, quantified, separated by an SDS-PAGE gel, and transferred to a PVDF blotting membrane (GE Healthcare, USA) for Western blot analysis following the manufacturer's protocol (Xue et al, 2017;Qin et al, 2018). After blocking with 5% nonfat milk and incubation with primary and second antibodies, the blotting membranes were examined using ECL luminescence reagent (Absin, Shanghai, China), and the images were acquired on a FluorChem Q System (Alpha Innotech, Cell Bioscienes, USA).…”

“…However, FOLFIRINOX has recently been associated with increased toxicity, mainly febrile neutropenia and diarrhea (Lambert et al, 2017). Numerous studies have unraveled the common molecular alterations occurring in PC, such as mutations in Kras, p53, and BRCA1 (Nag et al, 2013;Cicenas et al, 2017;Waters and Der, 2018), aberrant activation of wnt/bcatenin signaling and keap1/Nrf2 signaling (Qin et al, 2018;Kuo et al, 2019;Qin et al, 2019), and amplification and overexpression of MDM2, cyclin D1, USP7, and MDR1 (Qie and Diehl, 2016;Robey et al, 2018;Wang et al, 2019b;Dong et al, 2020;Qi et al, 2020), which play critical roles in the initiation, progression, metastasis, and chemoresistance of PC. Many targeted agents have been developed and evaluated in the preclinical and clinical settings (Karandish and Mallik, 2016).…”