Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer
AbstractBackground: 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. View Full-Text
- Supplementary File 1:
ZIP-Document (ZIP, 163 KB)
Share & Cite This Article
Manegold, P.; Lai, K.K.Y.; Wu, Y.; Teo, J.-L.; Lenz, H.-J.; Genyk, Y.S.; Pandol, S.J.; Wu, K.; Lin, D.P.; Chen, Y.; Nguyen, C.; Zhao, Y.; Kahn, M. Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer. Cancers 2018, 10, 95.
Manegold P, Lai KKY, Wu Y, Teo J-L, Lenz H-J, Genyk YS, Pandol SJ, Wu K, Lin DP, Chen Y, Nguyen C, Zhao Y, Kahn M. Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer. Cancers. 2018; 10(4):95.Chicago/Turabian Style
Manegold, Philipp; Lai, Keane K.Y.; Wu, Yongfeng; Teo, Jia-Ling; Lenz, Heinz-Josef; Genyk, Yuri S.; Pandol, Stephen J.; Wu, Kaijin; Lin, David P.; Chen, Yibu; Nguyen, Cu; Zhao, Yi; Kahn, Michael. 2018. "Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer." Cancers 10, no. 4: 95.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.