The FGF2-binding peptide P7 inhibits melanoma growth in vitro and in vivo
The FGF2-binding peptide P7 inhibits melanoma growth in vitro and in vivo
复制标题
DOI：
10.1007/s00432-012-1201-7
复制
发表时间：
2012-04
影响因子：
3.6
通讯作者：
Yonglin Yu;Susu Gao;Quchou Li;Cong Wang;Xinqiang Lai;Xilei Chen;Rui-xue Wang;J. Di;Tao Li;Wenhui Wang;Xiao-ping Wu
中科院分区：
文献类型：
--
作者：
Yonglin Yu;Susu Gao;Quchou Li;Cong Wang;Xinqiang Lai;Xilei Chen;Rui-xue Wang;J. Di;Tao Li;Wenhui Wang;Xiao-ping Wu
目的黑色素瘤是一种恶性肿瘤，与皮肤癌相关的死亡中大多数是由黑色素瘤引起的。成纤维细胞生长因子2 （FGF2）在黑色素瘤的生长和进展中起着重要作用。在本文中，我们试图通过探索FGF2结合肽（命名为P7）在体外和体内对黑色素瘤的抗肿瘤作用来评估FGF2结合肽作为一种有效的FGF2拮抗剂的治疗潜力。方法采用WST-1法测定细胞活力。采用碘化丙啶染色和流式细胞术检测细胞周期进展。Western blotting检测Erk1/2、P38、Akt、MEK的活化及凋亡相关蛋白的表达。P7对FGF2内化的影响通过分离细胞核和细胞质蛋白组分并进行Western blotting来评估。建立了携带异种移植黑色素瘤的雌性C57BL/6小鼠，并在体内评价P7的抗肿瘤作用。结果在本研究中，我们首次证明了P7肽能显著抑制fgf2诱导的黑色素瘤细胞系B16-F10的增殖。进一步研究发现，P7肽抑制FGF2体外刺激黑色素瘤细胞增殖的机制包括细胞周期阻滞在G0/G1期，阻断Erk1/2、P38和Akt级联的激活，抑制FGF2内化。最后，在小鼠黑色素瘤模型中，P7肽的处理导致体内肿瘤生长和血管生成明显抑制，这与阻断丝裂原激活的蛋白激酶信号激活，抑制抗凋亡Bcl-2蛋白和血管生成因子的表达有关。结论fgf2结合肽具有较强的抗增殖和抗血管生成活性，可能具有治疗黑色素瘤的潜力。
PurposeMelanoma is a malignant tumor and causes majority of deaths related to skin cancer. Fibroblast growth factor 2 (FGF2) greatly contributes to melanoma growth and progress. In this paper, we attempt to evaluate the therapeutic potential of FGF2-binding peptide (named P7) using as a potent FGF2 antagonist via exploration of its antitumor effect on melanoma in vitro and in vivo.MethodsCell viability was measured by WST-1. Cell cycle progression was determined by propidium iodide staining and flow cytometry. Western blotting was carried out to detect the activation of Erk1/2, P38, Akt, and MEK, and the expression of apoptosis-associated proteins. The influence of P7 on FGF2 internalization was assessed by separation of nuclear and cytoplasmic protein fractions followed by Western blotting. Female C57BL/6 mice bearing xenograft melanoma were established and used to evaluate the antitumor effect of P7 in vivo.ResultsIn this study, we first proved that P7 peptides significantly inhibited proliferation of FGF2-induced melanoma cell line B16-F10. Further investigations revealed that the mechanisms of P7 peptides inhibiting cell proliferation of melanoma cells stimulated with FGF2 in vitro involved cell cycle arrest at the G0/G1 phase, blockade of the activation of Erk1/2, P38, and Akt cascades, and inhibition of FGF2 internalization. Finally, treatment of P7 peptides in a murine melanoma model resulted in significant inhibition of tumor growth and angiogenesis in vivo, which was associated with blockade of mitogen-activated protein kinase signal activation, and suppression of the expressions of anti-apoptotic Bcl-2 protein and angiogenic factor in the melanoma tumors.ConclusionsThe FGF2-binding peptide with potent antiproliferation and anti-angiogenic activity may have therapeutic potential in melanoma.