The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction.
The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction.
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DOI：
10.18632/oncotarget.6399
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发表时间：
2016-01-12
期刊：
影响因子：
--
通讯作者：
Ramont L
中科院分区：
文献类型：
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作者：
Oudart JB;Doué M;Vautrin A;Brassart B;Sellier C;Dupont-Deshorgue A;Monboisse JC;Maquart FX;Brassart-Pasco S;Ramont L
XIX型胶原是与基底膜相关的次要胶原。它是第一次从横纹肌肉瘤的人cDNA文库中分离出来，属于FACIT家族（具有中断的三螺旋的原纤维相关胶原蛋白）。先前，我们证明了胶原XIX的NC 1结构域（NC 1（XIX））通过抑制黑色素瘤细胞的迁移和侵袭而对黑色素瘤细胞发挥抗肿瘤特性。在本工作中，我们首次鉴定了整合素αvβ3作为NC 1（XIX）的受体。此外，我们证明了NC 1（XIX）通过降低参与该途径的主要蛋白的磷酸化和活性来抑制FAK/PI 3 K/Akt/mTOR途径。另一方面，NC 1（XIX）通过降低其磷酸化程度诱导GSK 3 β活性增加。在黑色素瘤的发展中，靶向这一中心信号通路的治疗是有希望的，应该开发新的分子。NC 1（XIX）似乎具有设计新抗癌药物的潜力。
Type XIX collagen is a minor collagen associated with basement membranes. It was isolated for the first time in a human cDNA library from rhabdomyosarcoma and belongs to the FACITs family (Fibril Associated Collagens with Interrupted Triple Helices). Previously, we demonstrated that the NC1 domain of collagen XIX (NC1(XIX)) exerts anti-tumor properties on melanoma cells by inhibiting their migration and invasion. In the present work, we identified for the first time the integrin αvβ3 as a receptor of NC1(XIX). Moreover, we demonstrated that NC1(XIX) inhibits the FAK/PI3K/Akt/mTOR pathway, by decreasing the phosphorylation and activity of the major proteins involved in this pathway. On the other hand, NC1(XIX) induced an increase of GSK3β activity by decreasing its degree of phosphorylation. Treatments targeting this central signaling pathway in the development of melanoma are promising and new molecules should be developed. NC1(XIX) seems to have the potential for the design of new anti-cancer drugs.