Lycopene binding compromised PDGF-AA/-AB signaling and migration in smooth muscle cells and fibroblasts: prediction of the possible lycopene binding site within PDGF.
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-alpha 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 beta-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.
Chen
Ching-Pei
CP
Division of Cardiovascular Medicine, Changhua Christian Hospital, Changhua, Taiwan.
Hung
Chi-Feng
CF
Lee
Shao-Chen
SC
Lo
Huey-Ming
HM
Wu
Pi-Hui
PH
Wu
Wen-Bin
WB
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D000077214:Becaplermin; D001665:Binding Sites; D002338:Carotenoids / Q000008:administration & dosage / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000077276:Lycopene; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000975:Antioxidants; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D002338:Carotenoids; D017479:Receptors, Platelet-Derived Growth Factor; D000077276:Lycopene