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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

Authors :
Michael G. Kahn
Philipp C. Manegold
Stephen J. Pandol
Cu Nguyen
Yongfeng Wu
Jia-Ling Teo
David P. Lin
Yi-Bu Chen
Yi Zhao
Heinz-Josef Lenz
Kaijin Wu
Yuri Genyk
Keane K. Y. Lai
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.

Details

ISSN :
20726694
Volume :
10
Database :
OpenAIRE
Journal :
Cancers
Accession number :
edsair.doi.dedup.....76ea7b294f7019b0a29a82f078126f17
Full Text :
https://doi.org/10.3390/cancers10040095