TY - JOUR
T1 - Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells
AU - Chen, Dongmei
AU - Wirth, Keith M.
AU - Kizy, Scott
AU - Muretta, Joseph M.
AU - Markowski, Todd W.
AU - Yong, Peter
AU - Sheka, Adam
AU - Abdelwahab, Hisham
AU - Hertzel, Ann V.
AU - Ikramuddin, Sayeed
AU - Yamamoto, Masato
AU - Bernlohr, David A.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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. Implications: 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.
AB - 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. Implications: 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.
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U2 - 10.1158/1541-7786.MCR-22-0763
DO - 10.1158/1541-7786.MCR-22-0763
M3 - Article
C2 - 37115197
AN - SCOPUS:85166385421
SN - 1541-7786
VL - 21
SP - 836
EP - 848
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -