Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia

Li Ding, Geou Yarh Liou, Daniel M. Schmitt, Peter Storz, Jin San Zhang, Daniel D Billadeau

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression.

Original languageEnglish (US)
Pages (from-to)65-77
Number of pages13
JournalJournal of Pathology
Volume243
Issue number1
DOIs
StatePublished - Sep 1 2017

Fingerprint

Glycogen Synthase Kinase 3
Glycogen Synthase Kinases
Metaplasia
Pancreatitis
Ribosomal Protein S6 Kinases
Ceruletide
Neoplasms
Acinar Cells
Chronic Pancreatitis
Transgenic Mice
Pancreas
Adenocarcinoma
Cell Proliferation
Inflammation

Keywords

  • acinar-to-ductal metaplasia
  • glycogen synthase kinase-3β
  • KRas
  • pancreatic cancer
  • pancreatitis
  • S6 K

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia. / Ding, Li; Liou, Geou Yarh; Schmitt, Daniel M.; Storz, Peter; Zhang, Jin San; Billadeau, Daniel D.

In: Journal of Pathology, Vol. 243, No. 1, 01.09.2017, p. 65-77.

Research output: Contribution to journalArticle

Ding, Li ; Liou, Geou Yarh ; Schmitt, Daniel M. ; Storz, Peter ; Zhang, Jin San ; Billadeau, Daniel D. / Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia. In: Journal of Pathology. 2017 ; Vol. 243, No. 1. pp. 65-77.
@article{8ca6f9295bab4d248567e4b6d7b3322f,
title = "Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia",
abstract = "Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression.",
keywords = "acinar-to-ductal metaplasia, glycogen synthase kinase-3β, KRas, pancreatic cancer, pancreatitis, S6 K",
author = "Li Ding and Liou, {Geou Yarh} and Schmitt, {Daniel M.} and Peter Storz and Zhang, {Jin San} and Billadeau, {Daniel D}",
year = "2017",
month = "9",
day = "1",
doi = "10.1002/path.4928",
language = "English (US)",
volume = "243",
pages = "65--77",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia

AU - Ding, Li

AU - Liou, Geou Yarh

AU - Schmitt, Daniel M.

AU - Storz, Peter

AU - Zhang, Jin San

AU - Billadeau, Daniel D

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression.

AB - Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression.

KW - acinar-to-ductal metaplasia

KW - glycogen synthase kinase-3β

KW - KRas

KW - pancreatic cancer

KW - pancreatitis

KW - S6 K

UR - http://www.scopus.com/inward/record.url?scp=85026431061&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026431061&partnerID=8YFLogxK

U2 - 10.1002/path.4928

DO - 10.1002/path.4928

M3 - Article

C2 - 28639695

AN - SCOPUS:85026431061

VL - 243

SP - 65

EP - 77

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 1

ER -