Abstract
Platelet-derived growth factor (PDGF) is a potent stimulator of growth and motility of smooth muscle cells (SMCs) and fibroblasts. Abnormalities of PDGF/PDGF receptor (PDGFR) are thought to contribute to vascular diseases and malignancy. We previously showed that natural carotenoid lycopene can directly bind to PDGF-BB and affect its related functions in vascular SMCs. In this study we examined lycopene effect on PDGF-AA/-AB-induced signaling and migration in SMCs and fibroblasts. We found that lycopene inhibited PDGF-AA-induced SMC and fibroblast migration in a concentration-dependent manner. Lycopene reduced PDGF-AA signaling, including phosphorylation in PDGFR-α and its downstream protein kinases/enzymes. It also inhibited PDGF-AB-induced signaling and cell migration. However, lycopene did not affect PDGF-induced reactive oxygen species production and H2O2-induced PDGFR phosphorylation. The binding analysis revealed that lycopene but not β-carotene could directly bind to PDGF-AA in vitro and in plasma and this binding competitively inhibited lycopene interaction with PDGF-BB, suggesting that lycopene bound to PDGF-AA/-BB at a homologous/similar region within PDGF. Moreover, the docking and binding analyses predicted that the lycopene-binding region within PDGF was located at loop 2 region. Taken together, we provide here evidence that lycopene interacts with PDGF-AA/-AB and compromises their intracellular signaling, leading to a marked inhibition on PDGF-AA/-AB-induced migration in both SMCs and fibroblasts. We also predicted its binding region within PDGF and proved its anti-vascular injury effect in vivo. The results, together with our previous findings, suggest lycopene special affinity/effect for PDGF family and its possible application in prevention in vascular diseases and malignancy.
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Abbreviations
- ERK:
-
extracellular matrix-regulated kinase
- PDGF:
-
platelet-derived growth factor
- PDGFR-α:
-
PDGF receptor α
- PLC-γ:
-
phospholipase C-γ
- MAPK:
-
mitogen-activated protein kinase
- SMC(s):
-
smooth muscle cell(s)
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Acknowledgments
We thanked Dr. Su-Jane Wang for providing us with rat aorta. The work was supported by the research grants from Changhua Christian Hospital, Shin Kong Wu Ho-Su Memorial Hospital, and the National Science Council.
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Chen, CP., Hung, CF., Lee, SC. et al. Lycopene binding compromised PDGF-AA/-AB signaling and migration in smooth muscle cells and fibroblasts: prediction of the possible lycopene binding site within PDGF. Naunyn-Schmied Arch Pharmacol 381, 401–414 (2010). https://doi.org/10.1007/s00210-010-0501-1
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DOI: https://doi.org/10.1007/s00210-010-0501-1