Chiang Han-Sun, Wu Wen-Bin, Fang Jia-You, Chen Der-Fang, Chen Bing-Huei, Huang Chieh-Chen, Chen Ying-Ting, Hung Chi-Feng
School of Medicine, Fu-Jen Catholic University, No. 510, Chung-Cheng Road, Hsinchuang, Taipei Hsien, Taiwan.
Life Sci. 2007 Nov 10;81(21-22):1509-17. doi: 10.1016/j.lfs.2007.09.018. Epub 2007 Oct 2.
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.
在黑色素瘤的发生和发展过程中，血小板衍生生长因子（PDGF）被认为可调节微环境，尤其是基质成纤维细胞，从而有利于黑色素瘤的生长、侵袭和转移。番茄红素是一种在番茄中含量丰富的天然类胡萝卜素，已被证明可抑制多种癌细胞的增殖。然而，皮肤成纤维细胞和黑色素瘤细胞却很少受到关注。在本研究中，我们确定了番茄红素对基质成纤维细胞的影响及其与黑色素瘤细胞的相互作用。我们发现番茄红素可抑制PDGF-BB诱导的人Hs68皮肤成纤维细胞在明胶和胶原蛋白上的迁移。进一步分析表明，番茄红素可抑制PDGF-BB在人Hs68和原代培养的皮肤成纤维细胞中诱导的信号传导。番茄红素以浓度依赖性方式减弱了PDGF-BB诱导的血小板衍生生长因子受体β（PDGFR-β）、细胞外信号调节激酶1/2（ERK1/2）、p38和c-Jun氨基末端激酶（JNK）的磷酸化，而每种蛋白质的总表达不受影响。有趣的是，点杂交试验表明，番茄红素可在磷酸盐缓冲盐水（PBS）和人血浆中直接与人PDGF-BB结合，这表明番茄红素在体外和体内条件下均可与PDGF-BB结合。在功能研究中，番茄红素在非接触共培养系统中抑制了黑色素瘤诱导的成纤维细胞迁移，并减弱了由黑色素瘤衍生的条件培养基模拟的成纤维细胞中的信号传导。我们的结果提供了首个证据，表明番茄红素是基质成纤维细胞迁移的有效抑制剂，这种作用可能有助于其抗肿瘤活性。
