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Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer
Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer
- Source :
- Cancers, Cancers, vol 10, iss 4, Cancers, Vol 10, Iss 4, p 95 (2018), Cancers; Volume 10; Issue 4; Pages: 95
- Publication Year :
- 2018
- Publisher :
- MDPI AG, 2018.
-
Abstract
- Background: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector β-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that β-catenin’s differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer. Aim/methods: To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/β-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC. Results/conclusion: We report for the first time that K-Ras activation increases the CBP/β-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/β-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.
- Subjects :
- cancer stem cells
0301 basic medicine
Cancer Research
Oncology and Carcinogenesis
pancreatic cancer
self-renewal
medicine.disease_cause
lcsh:RC254-282
Article
03 medical and health sciences
Rare Diseases
Differentiation therapy
Pancreatic cancer
Survivin
Coactivator
Genetics
medicine
2.1 Biological and endogenous factors
Aetiology
Cancer
drug resistance
Chemistry
Wnt signaling pathway
Stem Cell Research
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Wnt signaling
3. Good health
n/a
030104 developmental biology
Oncology
Catenin
Cancer research
Stem Cell Research - Nonembryonic - Non-Human
Digestive Diseases
Carcinogenesis
Biotechnology
Subjects
Details
- ISSN :
- 20726694
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....76ea7b294f7019b0a29a82f078126f17
- Full Text :
- https://doi.org/10.3390/cancers10040095