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

Jason R. Pitarresi, Xin Liu, Alex Avendano, Katie A. Thies, Gina M. Sizemore, Anisha M. Hammer, Blake E. Hildreth, David J. Wang, Sarah A. Steck, Sydney Donohue, Maria C. Cuitiño, Raleigh D. Kladney, Thomas A. Mace, Jonathan J. Chang, Christina S. Ennis, Huiqing Li, Roger H Reeves, Seth Blackshaw, Jianying Zhang, Lianbo Yu & 12 others Soledad A. Fernandez, Wendy L. Frankel, Mark Bloomston, Thomas J. Rosol, Gregory B. Lesinski, Stephen F. Konieczny, Denis C. Guttridge, Anil K. Rustgi, Gustavo Leone, Jonathan W. Song, Jinghai Wu, Michael C. Ostrowski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere201800190
JournalLife Science Alliance
Volume1
Issue number5
DOIs
StatePublished - Jan 1 2018

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Erinaceidae
Phosphoric Monoester Hydrolases
tumor
phosphatase
Tumors
adenocarcinoma
fibroblasts
Degradation
degradation
neoplasms
Growth
Neoplasms
Fibroblasts
hyaluronoglucosaminidase
ubiquitin-protein ligase
Adenocarcinoma
extracellular matrix
protein kinases
proteomics
permeability

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Ecology
  • Health, Toxicology and Mutagenesis

Cite this

Pitarresi, J. R., Liu, X., Avendano, A., Thies, K. A., Sizemore, G. M., Hammer, A. M., ... Ostrowski, M. C. (2018). Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth. Life Science Alliance, 1(5), [e201800190]. https://doi.org/10.26508/lsa.201800190

Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth. / Pitarresi, Jason R.; Liu, Xin; Avendano, Alex; Thies, Katie A.; Sizemore, Gina M.; Hammer, Anisha M.; Hildreth, Blake E.; Wang, David J.; Steck, Sarah A.; Donohue, Sydney; Cuitiño, Maria C.; Kladney, Raleigh D.; Mace, Thomas A.; Chang, Jonathan J.; Ennis, Christina S.; Li, Huiqing; Reeves, Roger H; Blackshaw, Seth; Zhang, Jianying; Yu, Lianbo; Fernandez, Soledad A.; Frankel, Wendy L.; Bloomston, Mark; Rosol, Thomas J.; Lesinski, Gregory B.; Konieczny, Stephen F.; Guttridge, Denis C.; Rustgi, Anil K.; Leone, Gustavo; Song, Jonathan W.; Wu, Jinghai; Ostrowski, Michael C.

In: Life Science Alliance, Vol. 1, No. 5, e201800190, 01.01.2018.

Research output: Contribution to journalArticle

Pitarresi, JR, Liu, X, Avendano, A, Thies, KA, Sizemore, GM, Hammer, AM, Hildreth, BE, Wang, DJ, Steck, SA, Donohue, S, Cuitiño, MC, Kladney, RD, Mace, TA, Chang, JJ, Ennis, CS, Li, H, Reeves, RH, Blackshaw, S, Zhang, J, Yu, L, Fernandez, SA, Frankel, WL, Bloomston, M, Rosol, TJ, Lesinski, GB, Konieczny, SF, Guttridge, DC, Rustgi, AK, Leone, G, Song, JW, Wu, J & Ostrowski, MC 2018, 'Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth', Life Science Alliance, vol. 1, no. 5, e201800190. https://doi.org/10.26508/lsa.201800190
Pitarresi, Jason R. ; Liu, Xin ; Avendano, Alex ; Thies, Katie A. ; Sizemore, Gina M. ; Hammer, Anisha M. ; Hildreth, Blake E. ; Wang, David J. ; Steck, Sarah A. ; Donohue, Sydney ; Cuitiño, Maria C. ; Kladney, Raleigh D. ; Mace, Thomas A. ; Chang, Jonathan J. ; Ennis, Christina S. ; Li, Huiqing ; Reeves, Roger H ; Blackshaw, Seth ; Zhang, Jianying ; Yu, Lianbo ; Fernandez, Soledad A. ; Frankel, Wendy L. ; Bloomston, Mark ; Rosol, Thomas J. ; Lesinski, Gregory B. ; Konieczny, Stephen F. ; Guttridge, Denis C. ; Rustgi, Anil K. ; Leone, Gustavo ; Song, Jonathan W. ; Wu, Jinghai ; Ostrowski, Michael C. / Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth. In: Life Science Alliance. 2018 ; Vol. 1, No. 5.
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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.",
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AU - Pitarresi, Jason R.

AU - Liu, Xin

AU - Avendano, Alex

AU - Thies, Katie A.

AU - Sizemore, Gina M.

AU - Hammer, Anisha M.

AU - Hildreth, Blake E.

AU - Wang, David J.

AU - Steck, Sarah A.

AU - Donohue, Sydney

AU - Cuitiño, Maria C.

AU - Kladney, Raleigh D.

AU - Mace, Thomas A.

AU - Chang, Jonathan J.

AU - Ennis, Christina S.

AU - Li, Huiqing

AU - Reeves, Roger H

AU - Blackshaw, Seth

AU - Zhang, Jianying

AU - Yu, Lianbo

AU - Fernandez, Soledad A.

AU - Frankel, Wendy L.

AU - Bloomston, Mark

AU - Rosol, Thomas J.

AU - Lesinski, Gregory B.

AU - Konieczny, Stephen F.

AU - Guttridge, Denis C.

AU - Rustgi, Anil K.

AU - Leone, Gustavo

AU - Song, Jonathan W.

AU - Wu, Jinghai

AU - Ostrowski, Michael C.

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