Peroxiredoxin-1 Tyr194 phosphorylation regulates LOX-dependent extracellular matrix remodelling in breast cancer.
Animals
Breast Neoplasms
/ metabolism
Cell Line, Tumor
Collagen
/ metabolism
Extracellular Matrix
/ metabolism
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Mice
Peroxiredoxins
/ metabolism
Phosphorylation
Prognosis
Protein-Lysine 6-Oxidase
/ metabolism
Survival Analysis
Tyrosine
/ metabolism
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
19
01
2021
accepted:
21
07
2021
revised:
22
06
2021
pubmed:
15
8
2021
medline:
18
12
2021
entrez:
14
8
2021
Statut:
ppublish
Résumé
Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression. We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it. Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression. This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.
Sections du résumé
BACKGROUND
Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression.
METHODS
We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it.
RESULTS
Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression.
CONCLUSIONS
This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.
Identifiants
pubmed: 34389806
doi: 10.1038/s41416-021-01510-x
pii: 10.1038/s41416-021-01510-x
pmc: PMC8505437
doi:
Substances chimiques
Tyrosine
42HK56048U
Collagen
9007-34-5
PRDX1 protein, human
EC 1.11.1.15
Peroxiredoxins
EC 1.11.1.15
LOX protein, human
EC 1.4.3.13
Protein-Lysine 6-Oxidase
EC 1.4.3.13
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
1146-1157Subventions
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA131350
Pays : United States
Organisme : NCI NIH HHS
ID : R56 CA233817
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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