Progranulin/EphA2 axis: A novel oncogenic mechanism in bladder cancer.
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cisplatin
/ pharmacology
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Humans
Male
Phosphorylation
Progranulins
/ genetics
Receptor, EphA2
/ chemistry
Up-Regulation
Urinary Bladder Neoplasms
/ drug therapy
Bladder cancer
EphA2
Liprinα-1
Motility
Progranulin
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
13
02
2020
revised:
19
03
2020
accepted:
19
03
2020
pubmed:
18
5
2020
medline:
24
8
2021
entrez:
18
5
2020
Statut:
ppublish
Résumé
The growth factor progranulin plays a critical role in bladder cancer by modulating tumor cell motility and invasion. Progranulin regulates remodeling of the actin cytoskeleton by interacting with drebrin, an actin binding protein that regulates tumor growth. We previously discovered that progranulin depletion inhibits epithelial-to-mesenchymal transition and markedly reduces in vivo tumor growth. Moreover, progranulin depletion sensitizes urothelial cancer cells to cisplatin treatment, further substantiating a pro-survival function of progranulin. Until recently, the progranulin signaling receptor remained unidentified, precluding a full understanding of progranulin action in tumor cell biology. We recently identified EphA2, a member of a large family of receptor tyrosine-kinases, as the functional receptor for progranulin. However, it is not established whether EphA2 plays an oncogenic role in bladder cancer. Here we demonstrate that progranulin, and not ephrin-A1, the canonical ligand for EphA2, is the predominant EphA2 ligand in bladder cancer. Progranulin evoked Akt- and Erk1/2-mediated EphA2 phosphorylation at Ser897, which could drive bladder tumorigenesis. We discovered that EphA2 depletion severely blunted progranulin-dependent motility and anchorage-independent growth, and sensitized bladder cancer cells to cisplatin treatment. We further defined the mechanisms of progranulin/EphA2-dependent motility by identifying liprin-α1 as a novel progranulin-dependent EphA2 interacting protein and establishing its critical role in cell motility. The discovery of EphA2 as the functional signaling receptor for progranulin and the identification of novel downstream effectors offer a new avenue for understanding the underlying mechanism of progranulin action and may constitute novel clinical and therapeutic targets in bladder cancer.
Identifiants
pubmed: 32417448
pii: S0945-053X(20)30038-X
doi: 10.1016/j.matbio.2020.03.009
pmc: PMC8162889
mid: NIHMS1701549
pii:
doi:
Substances chimiques
EPHA2 protein, human
0
GRN protein, human
0
Progranulins
0
Receptor, EphA2
EC 2.7.10.1
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10-24Subventions
Organisme : NCI NIH HHS
ID : P30 CA056036
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA039481
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA047282
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA164462
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
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