RT Journal Article
SR Electronic
T1 Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800190
DO 10.26508/lsa.201800190
VO 1
IS 5
A1 Pitarresi, Jason R
A1 Liu, Xin
A1 Avendano, Alex
A1 Thies, Katie A
A1 Sizemore, Gina M
A1 Hammer, Anisha M
A1 Hildreth, Blake E
A1 Wang, David J
A1 Steck, Sarah A
A1 Donohue, Sydney
A1 Cuitiño, Maria C
A1 Kladney, Raleigh D
A1 Mace, Thomas A
A1 Chang, Jonathan J
A1 Ennis, Christina S
A1 Li, Huiqing
A1 Reeves, Roger H
A1 Blackshaw, Seth
A1 Zhang, Jianying
A1 Yu, Lianbo
A1 Fernandez, Soledad A
A1 Frankel, Wendy L
A1 Bloomston, Mark
A1 Rosol, Thomas J
A1 Lesinski, Gregory B
A1 Konieczny, Stephen F
A1 Guttridge, Denis C
A1 Rustgi, Anil K
A1 Leone, Gustavo
A1 Song, Jonathan W
A1 Wu, Jinghai
A1 Ostrowski, Michael C
YR 2018
UL http://www.life-science-alliance.org/content/1/5/e201800190.abstract
AB 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.