Dataset Information

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

ACCESS DATA

Publications

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

Qin Jiang-Jiang JJ Wang Wei W Li Xin X Deokar Hemantkumar H Buolamwini John K JK Zhang Ruiwen R

Frontiers in pharmacology 20180117

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 ...[more]

PMID: 29387014

Similar Datasets

Project description:BackgroundPancreatic cancer is one of the most lethal disease with highly fatal and aggressive properties. Lymph node ratio (LNR), the ratio of the number of metastatic lymph nodes to the total number of examined lymph nodes, is an important index to assess lymphatic metastasis and predict prognosis, but the molecular mechanism underlying high LNR was unclear.MethodsGene expression and clinical information data of pancreatic cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Patients in TCGA were averagely divided into low and high LNR groups. Then, Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to build co-expression network to explore LNR-related modules and hub genes. GO and KEGG analysis was performed to find key pathways related to lymph node metastasis. Next, GSE101448 and the overall survival data in TCGA was employed to further select significant genes from hub genes. Considering the key role of CHRNB2 in LNR and survival, gene set enrichment analysis (GSEA) was applied to find pathways related to CHRNB2 expression in pancreatic cancer. The contribution of CHRNB2 to migrative and invasive ability of pancreatic cancer cells was confirmed by Transwell assays. We finally explored the role of CHRNB2 in EMT and β-catenin pathway via Western Blot.ResultsHigh LNR was significantly related to high T stages and poor prognosis. In WGCNA, 14 hub genes (COL5A1, FN1, THBS2, etc.) were positively related to high LNR, 104 hub genes (FFAR1, SCG5, TMEM63C, etc.) were negatively related to high LNR. After taking the intersection with GSE101448, 13 genes (CDK5R2, SYT7, CACNA2D2, etc.) which might prevent lymph node metastasis were further selected. Among them, CHRNB2 showed the strongest relationship with long survival. Moreover, CHRNB2 also negatively related to the T stages and LNR. Next, knockdown of CHRNB2 expression could acetylcholine (ACh)-independently increase the migration and invasion of pancreatic cancer cells, while CHRNB2 overexpression ACh-independently decrease the migration and invasion of pancreatic cancer cells. For exploring the underlying mechanism, CHRNB2 downregulated β-catenin pathway might through controlling its upstream regulators such as SOX6, SRY, SOX17, and TCF7L2.ConclusionsCHRNB2 negatively relates to lymph node metastasis in pancreatic cancer patients. CHRNB2 could inhibit β-catenin pathway, EMT, migration and invasion of pancreatic cancer cells via ACh-independent mechanism.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets