Lycopene inhibits PDGF-BB-induced signaling and migration in human dermal fibroblasts through interaction with PDGF-BB

In melanoma development and progression, platelet-derived growth factor (PDGF) has been suggested to modulate the microenvironment, especially stromal fibroblasts, to the benefit of melanoma growth, invasion, and metastasis. Lycopene, a natural carotenoid that is abundant in tomato, has been shown to inhibit proliferation of several types of cancer cells. However, little attention has been paid to skin fibroblasts and melanoma cells. In the present study, we determined the effects of lycopene on stromal fibroblasts and their interactions with melanoma cells. We found that lycopene inhibited PDGF-BB-induced human Hs68 skin fibroblast migration on gelatin and collagen. Further analysis showed that lycopene inhibited PDGF-BB-induced signaling in human Hs68 and primary cultured skin fibroblasts. PDGF-BB-induced phosphorylation of PDGF receptor beta (PDGFR-beta), extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK) was attenuated by lycopene in a concentration-dependent manner, whereas the total expression of each protein was not affected. Interestingly, dot binding assay revealed that lycopene could directly bind to human PDGF-BB in PBS and human plasma, indicating that lycopene can bind to PDGF-BB in both in vitro and in vivo conditions. In functional studies, lycopene inhibited melanoma-induced fibroblast migration in a noncontact coculture system and attenuated signaling in fibroblasts simulated by melanoma-derived conditioned medium. Our results provide the first evidence showing that lycopene is an effective inhibitor of migration of stromal fibroblasts and this effect may contribute to its antitumor activity. (c) 2007 Elsevier Inc. All rights reserved.