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

• Type of Material: Article
• Authors: Jason R. Pitarresi, Ohio State University; Xin Liu, Ohio State University; Alex Avendano, Ohio State University; Katie A Thies, Medical University of South Carolina; Gina M Sizemore, Ohio State University; Anisha M Hammer, Ohio State University; Blake E Hildreth, Medical University of South Carolina; David J Wang, Medical University of South Carolina; Sarah A Steck, Ohio State University; Sydney Donohue, Ohio State University; Maria C Cuitiño, Medical University of South Carolina; Gregory Lesinski, Emory University
• Language: English
• Date: 2018-01-01
• Publisher: Life Science Alliance
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Pitarresi et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.26508/lsa.201800190
• Title of Journal or Parent Work: Life Science Alliance
• ISSN: 2575-1077
• Volume: 1
• Issue: 5
• Start Page: e201800190
• End Page: e201800190
• Grant/Funding Information: This work was also supported by the Department of Defense (W81XWH-14-1-0040, GM Sizemore), Pelotonia Fellowship Program (JR Pitarresi, GM Sizemore, A Avendano, JJ Chang, and CS Ennis), and the OSU Institute for Materials Research.; This study was supported by National Institutes of Health grants PO1 CA097189 (MC Ostrowski and G Leone), NRSA F31 CA189757 (JR Pitarresi), NRSA F32 CA221094 (JR Pitarresi), American Cancer Society IRG-67-003-50 (JW Song), American Heart Association 15SDG25480000 (JW Song), and R01 CA124586 (SF Konieczny).; Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the Pelotonia Fellowship Program.
• Keywords: stromal hedgehog signaling; proteasomal degradation; tumor growth; RNF5-mediation; pancreatic cancer; PTEN
• Research Categories: Health Sciences, Oncology

Abstract

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.