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PNAS:改造信号蛋白可阻止黑素瘤细胞转移

来源:EurekAlert! 2009-11-11 10:20

一种经过修改的信号传导蛋白分子可能有能力阻断导致黑素瘤细胞转移的失误。皮肤黑素瘤导致相对较少的癌症,但是它们的传播倾向意味着这种疾病导致了皮肤癌死亡的大部分。

Victoria Sherwood及其同事调查了阻断Wnt5a分子的方法。这种分子的信号能增加细胞运动并导致黑素瘤的转移。这组作者最初尝试通过上级调控者关闭Wnt5a的表达,结果被证明无效,这导致这组科学家把目标直接对准Wnt5a信号传导。他们然后开发出了一种称为Box5的缩氨酸,它可能有能力阻断Wnt5的信号传导活动。在黑素瘤细胞系的测试中,这种Box5分子通过抑制Wnt5a的钙信号传导(它对于细胞入侵至关重要)从而消除了这些细胞的迁移和入侵。这组科学家说,Box5的这种直接效应提示,它可能对于开发针对转移性黑素瘤和其他Wnt5a信号传导迅速增殖的癌症的疗法有帮助。(生物谷Bioon.com)

生物谷推荐原始出处:

PNAS November 9, 2009, doi: 10.1073/pnas.0909409106

A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion

Veronika Jenei1,2, Victoria Sherwood1,3, Jillian Howlin, Rickard Linnskog, Annette S?fholm, Lena Axelsson and Tommy Andersson

Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Malm? University Hospital, SE-20502 Malm?, Sweden

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, TGFβ1, controlled the expression of Wnt5a, but due to the unpredictable effects of TGFβ1 signaling on melanoma cell motility, targeting Wnt5a signaling via TGFβ1 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.

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