A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion
A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion
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DOI：
10.1073/pnas.0909409106
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发表时间：
2009-11-17
影响因子：
11.1
通讯作者：
Andersson, Tommy
中科院分区：
文献类型：
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作者：
Jenei, Veronika;Sherwood, Victoria;Andersson, Tommy
Wnt5a在肿瘤进展中的重要作用强调了开发能够针对Wnt5a介导的细胞反应的分子的必要性。在侵袭性皮肤癌、黑色素瘤中，Wnt5a的高表达促进了细胞的运动，并推动了转移。有两种方法可以用来抵消这些影响：抑制Wnt5a的表达或直接阻断Wnt5a信号。我们已经在黑色素瘤细胞系A2058和HTB63中研究了这两种选择。两者都表达Frizzled5，它被认为是黑色素瘤细胞中Wnt5a的受体。然而，只有HTB63细胞表达和分泌Wnt5a。在这些细胞中，细胞因子转化生长因子β1控制Wnt5a的表达，但由于转化生长因子β1信号对黑色素瘤细胞运动的不可预测的影响，通过转化生长因子β1靶向Wnt5a信号是不合适的策略。因此，我们尝试直接针对WNT5a信号。外源性WNT5a刺激A2058细胞增加黏附、迁移和侵袭，这些都是肿瘤转移的关键成分，WNT5a衍生的N-丁氧羰基六肽(Met-Asp-Gly-Cys-Glu-Leu；0.766 kDa)取消了这些反应。Box5还能抑制表达Wnt5a的HTB63黑色素瘤细胞的侵袭和迁移。Box5通过直接抑制Wnt5a诱导的蛋白激酶C和钙信号通路来拮抗Wnt5a对黑色素瘤细胞迁移和侵袭的影响，我们直接证明后者是细胞侵袭所必需的。Box5多肽直接抑制Wnt5a信号，代表了一种抗转移治疗的方法，用于其他快速进展的黑色素瘤和其他Wnt5a刺激的侵袭性癌症。
The influential role of Wnt5a in tumor progression underscores the requirement for developing molecules that can target Wnt5a-mediated cellular responses. In the aggressive skin cancer, melanoma, elevated Wnt5a expression promotes cell motility and drives metastasis. Two approaches can be used to counteract these effects: inhibition of Wnt5a expression or direct blockade of Wnt5a signaling. We have investigated both options in the melanoma cell lines, A2058 and HTB63. Both express Frizzled-5, which has been implicated as the receptor for Wnt5a in melanoma cells. However, only the HTB63 cell line expresses and secretes Wnt5a. In these cells, the cytokine, TGF beta 1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGF beta 1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGF beta 1 was an unsuitable strategy to pursue. We therefore attempted to target Wnt5a signaling directly. Exogenous Wnt5a stimulation of A2058 cells increased adhesion, migration and invasion, all crucial components of tumor metastasis, and the Wnt5a-derived N-butyloxycarbonyl hexapeptide (Met-Asp-Gly-Cys-Glu-Leu; 0.766 kDa) termed Box5, abolished these responses. Box5 also inhibited the basal migration and invasion of Wnt5a-expressing HTB63 melanoma cells. Box5 antagonized the effects of Wnt5a on melanoma cell migration and invasion by directly inhibiting Wnt5a-induced protein kinase C and Ca2+ signaling, the latter of which we directly demonstrate to be essential for cell invasion. The Box5 peptide directly inhibits Wnt5a signaling, representing an approach to anti-metastatic therapy for otherwise rapidly progressive melanoma, and for other Wnt5a-stimulated invasive cancers.