Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells.

Mingtian Che,Raul A Urrutia,Stephen J Pandol,Jia-Ling Teo,Richard T Waldron,Soo-Mi Kweon,Keane K Y Lai,Laleh G Melstrom,Yate-Ching Yuan,Aurelia Lugea

doi:10.3390/cancers12061476

Abstract

Background: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. Methods: To investigate the role of the CBP/β-catenin signaling pathway in the activation of PSCs, we have treated mouse and human PSCs with the small molecule specific CBP/β-catenin antagonist ICG-001 and examined the effects of treatment on parameters of activation. Results: We report for the first time that CBP/β-catenin antagonism suppresses activation of PSCs as evidenced by their decreased proliferation, down-regulation of “activation” markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ) which is associated with quiescence, and reduced migration; additionally, CBP/β-catenin antagonism also suppresses PSC-induced migration of cancer cells. Conclusion: CBP/β-catenin antagonism represents a novel therapeutic strategy for suppressing PSC activation and may be effective at countering PSC promotion of pancreatic cancer.

Highlights

Pancreatic cancer, predominantly comprised of pancreatic ductal adenocarcinoma (PDAC), ranks as the 4th leading cause of cancer deaths in both men and women in the United States, with ~52% of pancreatic cancer patients being diagnosed at an advanced stage of disease for which 5-year survival is a dismal 3% [1]
We report for the first time that the small molecule specific cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin antagonist ICG-001 suppresses activation of pancreatic stellate cells (PSCs) as evidenced by their decreased proliferation, down-regulation of activation markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ), which is associated with quiescence, and reduced migration; and that migration of PDAC cells is reduced when co-cultured with PSCs which have been pre-treated with ICG-001
We found that ICG-001 inhibited proliferation of immortalized mouse pancreatic stellate cells (imPSC) and immortalized human pancreatic stellate cells (ihPSC), as assessed by CellTiter-Glo proliferation assay (Figure 1A,B), microscopy (Figure 1C,D), and cell counting (Figure 1E,F)

Summary

Introduction

Pancreatic cancer, predominantly comprised of pancreatic ductal adenocarcinoma (PDAC), ranks as the 4th leading cause of cancer deaths in both men and women in the United States, with ~52% of pancreatic cancer patients being diagnosed at an advanced stage of disease for which 5-year survival is a dismal 3% [1]. Treatments for PDAC, which traditionally have focused on targeting pancreatic tumor cells (i.e., parenchymal cells), have been insufficient or have failed for the most part [2,3]. It has been recognized that activated pancreatic stellate cells (PSCs) (i.e., stromal cells), which are characterized by increased proliferation, up-regulation of “activation” markers, and enhanced migration, promote PDAC progression [2,3,4]. Cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. CBP/β-catenin antagonism suppresses activation of PSCs as evidenced by their decreased proliferation, down-regulation of “activation” markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type. I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ) which is associated with quiescence, and reduced migration; CBP/β-catenin antagonism suppresses PSC-induced migration of cancer cells

Methods

Results

Discussion

Conclusion