Title

Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth

Authors

Jason R. Pitarresi, The Ohio State University
Xin Liu, The Ohio State University
Alex Avendano, The Ohio State University Comprehensive Cancer Center
Katie A. Thies, Medical University of South Carolina
Gina M. Sizemore, The Ohio State University Comprehensive Cancer Center
Anisha M. Hammer, The Ohio State University
Blake E. Hildreth, Medical University of South Carolina
David J. Wang, Medical University of South Carolina
Sarah A. Steck, The Ohio State University Comprehensive Cancer Center
Sydney Donohue, The Ohio State University Comprehensive Cancer Center
Maria C. Cuitiño, Medical University of South Carolina
Raleigh D. Kladney, The Ohio State University Comprehensive Cancer Center
Thomas A. Mace, The Ohio State University
Jonathan J. Chang, The Ohio State University Comprehensive Cancer Center
Christina S. Ennis, The Ohio State University Comprehensive Cancer Center
Huiqing Li, Johns Hopkins School of Medicine
Roger H. Reeves, Johns Hopkins School of Medicine
Seth Blackshaw, Johns Hopkins School of Medicine
Jianying Zhang, The Ohio State University
Lianbo Yu, The Ohio State University
Soledad A. Fernandez, The Ohio State University
Wendy L. Frankel, The Ohio State University
Mark Bloomston, The Ohio State University
Thomas J. Rosol, Ohio University
Gregory B. Lesinski, Emory University
Stephen F. Konieczny, College of Science
Denis C. Guttridge, The Ohio State University
Anil K. Rustgi, Penn Medicine
Gustavo Leone, Medical University of South Carolina
Jonathan W. Song, The Ohio State University Comprehensive Cancer Center
Jinghai Wu, The Ohio State University Comprehensive Cancer Center
Michael C. Ostrowski, Medical University of South Carolina

Document Type

Article

Publication Date

1-1-2018

Abstract

© 2018 Pitarresi et al. The contribution of the tumor microenvironment to pancreatic ductal adenocarcinoma (PDAC) development is currently unclear. We therefore examined the consequences of disrupting paracrine Hedgehog (HH) signaling in PDAC stroma. Herein, we show that ablation of the key HH signaling gene Smoothened (Smo) in stromal fibroblasts led to increased proliferation of pancreatic tumor cells. Furthermore, Smo deletion resulted in proteasomal degradation of the tumor suppressor PTEN and activation of oncogenic protein kinase B (AKT) in fibroblasts. An unbiased proteomic screen identified RNF5 as a novel E3 ubiquitin ligase responsible for degradation of phosphatase and tensin homolog (PTEN) in Smo-null fibroblasts. Ring Finger Protein 5 (Rnf5) knockdown or pharmacological inhibition of glycogen synthase kinase 3β (GSKβ), the kinase that marks PTEN for ubiquitination, rescued PTEN levels and reversed the oncogenic phenotype, identifying a new node of PTEN regulation. In PDAC patients, low stromal PTEN correlated with reduced overall survival. Mechanistically, PTEN loss decreased hydraulic permeability of the extracellular matrix, which was reversed by hyaluronidase treatment. These results define non-cell autonomous tumor-promoting mechanisms activated by disruption of the HH/PTEN axis and identifies new targets for restoring stromal tumor-suppressive functions.

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