mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src
mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src
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DOI：
10.1073/pnas.0808171105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
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作者：
Boukerche, Habib;Su, Zao-zhong;Fisher, Paul B.
含有PDZ结构域的支架蛋白MDA-9/Syntenin对人类黑色素瘤和其他肿瘤中的癌细胞进展起着积极的调节作用。MDA-9/Syntenin通过改变已定义的生化和信号通路来调节细胞的运动和侵袭，包括粘着斑激酶(FAK)、p38丝裂原活化蛋白激酶(MAPK)和核因子-kappa B，但目前还不清楚MDA-9/Syntenin如何组织这些多蛋白信号复合体。利用临床相关的人类黑色素瘤模型，我们证明了MDA-9/Syntenin与c-Src在物理上相互作用，这种相互作用与FAK/c-Src复合体的形成和c-Src的激活有关。抑制MDA-9/Syntenin，使用表达反义MDA-9/Syntenin的腺病毒或添加c-Src siRNA，在人黑色素瘤动物转移模型中抑制黑色素瘤细胞的迁移、锚定非锚定生长和肿瘤细胞的自发扩散。这些数据与一个模型相一致，在该模型中，MDA-9/Syntenin与c-Src相互作用促进活性的FAK/c-Src信号复合体的形成，导致肿瘤细胞增强侵袭和转移扩散。这些挑衅性的发现强调了MDA-9/Syntenin及其相互作用的伙伴是干预转移的有希望的治疗靶点。
The scaffold PDZ-domain containing protein mda-9/syntenin functions as a positive regulator of cancer cell progression in human melanoma and other tumors. mda-9/Syntenin regulates cell motility and invasion by altering defined biochemical and signaling pathways, including focal adhesion kinase (FAK), p38 mitogen-activated protein kinase (MAPK) and NF-kappa B, but precisely how mda-9/syntenin organizes these multiprotein signaling complexes is not well understood. Using a clinically relevant human melanoma model, we demonstrate that mda-9/syntenin physically interacts with c-Src and this communication correlates with an increase in FAK/c-Src complex formation and c-Src activation. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin or addition of c-Src siRNA, suppresses melanoma cell migration, anchorage-independent growth, and spontaneous tumor cell dissemination in vivo in a human melanoma animal metastasis model. These data are compatible with a model wherein interaction of MDA-9/syntenin with c-Src promotes the formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread. These provocative findings highlight mda-9/syntenin and its interacting partners as promising therapeutic targets for intervention of metastasis.