Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis

Liu, S; Tackmann, Nicole R.; Yang, Jing; Zhang, Yingao

doi:10.1038/onc.2016.301

Cited by 30 publications

(21 citation statements)

References 53 publications

(70 reference statements)

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“…The deregulation of the Wnt/β-catenin signaling pathway in human cancer has been attributed to the inactivation of APC tumor suppressor ( Sansom et al, 2004 ). A recent study has indicated that the ribosomal protein-MDM2-p53 pathway is another crucial mediator of APC loss-induced tumorigenesis ( Liu et al, 2017 ). Herein, dual inhibition of β-catenin and MDM2 may display a synergistic anticancer activity and could be a promising therapeutic strategy for advanced pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Qin

Wang

et al. 2018

Front. Pharmacol.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Qin

Wang

et al. 2018

Front. Pharmacol.

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“…Also, disparity between our findings on SW13 and H295R cells supports the notion, as those cells represent different types of adrenocortical cancer. Our findings also raise questions regarding crosstalk between canonical Wnt signaling and MDM2, which are previously suggested to be very loosely connected . Scholars suggest disruption of the RP‐MDM2‐p53 pathway accelerates APC loss‐induced colorectal tumorigenesis, yet how much APC loss can simulate CTNNB1 mutation in the ACC context remains undetermined.…”

Section: Discussionmentioning

confidence: 73%

Nutlin‐3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation

et al. 2018

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Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In‐silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin‐3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin‐3a inhibited cellular proliferation in ACC cell line NCI‐H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin‐3a induced cell apoptosis and G1 cell‐cycle arrest in NCI‐H295R cells. Nutlin‐3a also decreased cellular migration and inhibited epithelial‐to‐mesenchymal transition (EMT) process in terms of EMT index. Nutlin‐3a resulted in decreased β‐catenin level independent of p53 level in NCI‐H295R but not SW13 cells. We also evaluated the effect of Nutlin‐3a on hormonal secretion of NCI‐H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin‐3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin‐3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta‐Catenin signaling in ACC warrants further study.

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“…APC loss of function, especially due frameshift and nonsense mutations, or down-regulation is a major cause in the colorectal tumorigenesis and it’s been proposed its loss is sufficient to induce carcinogenesis [ 42 , 43 ]. Our results indicate that APC down-regulation is also an important risk factor to the development of gastric cancer and that this gene may have a crucial function in gastrointestinal malignant neoplasia.…”

Section: Discussionmentioning

confidence: 99%

APC gene is modulated by hsa-miR-135b-5p in both diffuse and intestinal gastric cancer subtypes

et al. 2018

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BackgroundSeveral genetic and epigenetic alterations are related to the development and progression of Gastric Cancer (GC), one of those being the deregulated microRNA (miRNA) expression profile. miRNAs are small noncoding RNAs that negatively regulate the expression of thousands of genes, including oncogenes and tumor suppressor genes. Our group identified, in previous studies, some miRNAs that are differentially expressed in GC when compared to the gastric mucosa without cancer, including hsa-miR-29c and hsa-miR-135b. The aim of the study was to modulate the expression of the miRNAs hsa-miR-29c-5p and hsa-miR-135b-5p and evaluate the expression of their target genes in 2D and 3D cell cultures.Methodshsa-miR-29c-5p and hsa-miR-135b-5p expression profiles were modulated by transfecting mimics and antimiRs, respectively, in 2D and 3D cell cultures. The expression of the proteins coded by the genes CDC42, DNMT3A (target genes of hsa-miR-29c-5p) and APC (target gene of hsa-miR-135b-5p) were measured by Western Blot.ResultsResults showed that mimics and antimiRs transfection significantly altered the expression of both miRNAs, increasing the expression of hsa-miR-29c-5p and reducing the expression of hsa-miR-135b-5p, especially in the 3D culture of the cell lines. When analyzing the proteins expression, we observed that AGP01 and AGP03 cell lines transfected with mimics had a reduction in the levels of CDC42 and DNMT3A and all three cell lines transfected with antimiRs had an increase in the expression of the protein APC.ConclusionWe concluded that three-dimensional culture can be a more representative in vitro model that resembles better the in vivo reality. Our results also showed that hsa-miR-29c-5p is an important regulator of CDC42 and DNMT3A genes in the intestinal subtype gastric cancer and hsa-miR-135b-5p regulates the APC gene in both intestinal and diffuse subtypes of GC. Dysregulation in their expression, and consequently in their respectively signaling pathways, shows how these miRNAs can influence the carcinogenesis of different histological subtypes of gastric cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4980-7) contains supplementary material, which is available to authorized users.

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Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis

Cited by 30 publications

References 53 publications

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

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

Nutlin‐3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation

APC gene is modulated by hsa-miR-135b-5p in both diffuse and intestinal gastric cancer subtypes

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