Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells.
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
01 08 2023
01 08 2023
Historique:
received:
27
09
2022
revised:
19
01
2023
accepted:
26
04
2023
pmc-release:
01
02
2024
medline:
2
8
2023
pubmed:
28
4
2023
entrez:
28
4
2023
Statut:
ppublish
Résumé
Fatty acid binding protein 4 (FABP4) is a secreted adipokine linked to obesity and progression of a variety of cancers. Obesity increases extracellular FABP4 (eFABP4) levels in animal models and in obese breast cancer patients compared with lean healthy controls. Using MCF-7 and T47D breast cancer epithelial cells, we show herein that eFABP4 stimulates cellular proliferation in a time and concentration dependent manner while the non-fatty acid-binding mutant, R126Q, failed to potentiate growth. When E0771 murine breast cancer cells were injected into mice, FABP4 null animals exhibited delayed tumor growth and enhanced survival compared with injections into control C57Bl/6J animals. eFABP4 treatment of MCF-7 cells resulted in a significant increase in phosphorylation of extracellular signal-regulated kinase 1/2 (pERK), transcriptional activation of nuclear factor E2-related factor 2 (NRF2) and corresponding gene targets ALDH1A1, CYP1A1, HMOX1, SOD1 and decreased oxidative stress, while R126Q treatment did not show any effects. Proximity-labeling employing an APEX2-FABP4 fusion protein revealed several proteins functioning in desmosomes as eFABP4 receptor candidates including desmoglein (DSG), desmocollin, junction plankoglobin, desomoplankin, and cytokeratins. AlphaFold modeling predicted an interaction between eFABP4, and the extracellular cadherin repeats of DSG2 and pull-down and immunoprecipitation assays confirmed complex formation that was potentiated by oleic acid. Silencing of DSG2 in MCF-7 cells attenuated eFABP4 effects on cellular proliferation, pERK levels, and ALDH1A1 expression compared with controls. These results suggest desmosomal proteins, and in particular desmoglein 2, may function as receptors of eFABP4 and provide new insight into the development and progression of obesity-associated cancers.
Identifiants
pubmed: 37115197
pii: 726208
doi: 10.1158/1541-7786.MCR-22-0763
pmc: PMC10524127
mid: NIHMS1898353
doi:
Substances chimiques
Desmoglein 2
0
Fatty Acid-Binding Proteins
0
Cadherins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
836-848Subventions
Organisme : NIDDK NIH HHS
ID : T32 DK108733
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK053189
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK053189
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG069819
Pays : United States
Organisme : NIDDK NIH HHS
ID : R21 DK122832
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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