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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.
Author Information (click to view)

Manegold P, Lai KKY, Wu Y, Teo JL, Lenz HJ, Genyk YS, Pandol SJ, Wu K, Lin DP, Chen Y, Nguyen C, Zhao Y, Kahn M,


Manegold P, Lai KKY, Wu Y, Teo JL, Lenz HJ, Genyk YS, Pandol SJ, Wu K, Lin DP, Chen Y, Nguyen C, Zhao Y, Kahn M, (click to view)

Manegold P, Lai KKY, Wu Y, Teo JL, Lenz HJ, Genyk YS, Pandol SJ, Wu K, Lin DP, Chen Y, Nguyen C, Zhao Y, Kahn M,

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Cancers 2018 03 2910(4) pii 10.3390/cancers10040095

Abstract
BACKGROUND
Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant, 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 thatactivation 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 ofand survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.

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