Laminin-1-derived scrambled peptide AG73T disaggregates laminin-1-induced ovarian cancer cell spheroids and improves the efficacy of cisplatin.
Laminin-1-derived scrambled peptide AG73T disaggregates laminin-1-induced ovarian cancer cell spheroids and improves the efficacy of cisplatin.
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Laminin-1 衍生的乱序肽 AG73T 可分解 laminin-1 诱导的卵巢癌细胞球体并提高顺铂的疗效。
DOI：
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发表时间：
2008
影响因子：
5.2
通讯作者：
F. Kotsuji
中科院分区：
文献类型：
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作者：
Y. Yoshida;T. Kurokawa;Yukiko Nishikawa;Makoto Orisa;H. Kleinman;F. Kotsuji
我们先前发现层粘连蛋白-1衍生的合成肽AG 73（LQVQLSIR）促进卵巢癌细胞的体内转移。我们现在已经研究了这种转移促进肽在体外使用TAC 3卵巢癌细胞，显示锚定非依赖性生长和形成多细胞球体的作用。我们的目标是更好地了解这种肽如何调节体内转移。我们发现，外源性添加层粘连蛋白-1或肽AG 73刺激球状体的形成和生长。Western blot分析表明，层粘连蛋白-1增强整合素β 1的表达，AG 73肽增强syndecan-1和下游效应物的表达，包括丝裂原活化蛋白激酶（MAPK）和细胞外信号相关激酶（ERK），以及磷脂酰肌醇（PI）-3激酶/AKT活性信号传导。可溶性肽AG 73 T，其为AG 73的混杂肽，能够解聚层粘连蛋白-1诱导的球状体。此外，解聚的细胞对顺铂的敏感性是完整球体的两倍。AG 73 T肽在层粘连蛋白-1的存在下抑制整合素β 1及其下游效应物的表达，包括MAPK/ERK和PI 3/AKT活性信号传导。MEK抑制剂U 0126在层粘连蛋白-1和AG 73 T两者的存在下比在单独层粘连蛋白-1的存在下更有效地减少TAC 3细胞生长。在存在层粘连蛋白-1和AG 73 T的情况下，用LY 294002抑制PI 3-K级联反应也更有效。在AG 73 T存在下对顺铂的敏感性增加可能是由于药物对自由漂浮细胞的生物利用度高于球状体。这些发现表明AG 73 T在卵巢癌中的新功能，并有助于确定卵巢癌球体形成和扩散的重要机制。
We found previously that the laminin-1-derived synthetic peptide AG73 (LQVQLSIR) promoted ovarian cancer cell metastasis in vivo. We have now studied the role of this metastasis-promoting peptide in vitro using TAC3 ovarian cancer cells, which display anchorage-independent growth and form multicellular spheroids. Our goal is to better understand how this peptide can regulate metastasis in vivo. We found that the exogenous addition of either laminin-1 or peptide AG73 stimulated the formation and growth of the spheroids. Western blot analysis indicated that laminin-1 enhanced the expression of integrin beta1, and that AG73 peptide enhanced expression of syndecan-1 and downstream effectors, including mitogen-activated protein kinase (MAPK) and extracellular signal-related kinase (ERK), and also phosphatidylinositol (PI)-3 kinase/AKT activity signaling. The soluble peptide AG73T, which is a scramble peptide of AG73, was able to disaggregate the laminin-1-induced spheroids. Furthermore, the disaggregated cells were twice as sensitive to cisplatin as the intact spheroids. The AG73T peptide in the presence of laminin-1 suppressed expression of integrin beta1 and its downstream effectors, including MAPK/ERK and PI3/AKT activity signaling. The MEK inhibitor U0126 reduced TAC3 cell growth more effectively in the presence of both laminin-1 and AG73T than in the presence of laminin-1 alone. Inhibition of the PI3-K cascade with LY294002 was also more effective in the presence of laminin-1 and AG73T. The increased sensitivity to cisplatin in the presence of AG73T may be due to the greater bioavailability of the drug to the free-floating cells over the spheroids. These findings suggest a novel function of AG73T in ovarian cancer and help to define mechanisms important in ovarian cancer spheroid formation and spread.
Raji 细胞扩散过程中 Syndecan-1 信号独立于 β1 整合素。
影响因子：
3.7
作者：
Lebakken,CS;McQuade,KJ;Rapraeger,AC
通讯作者：
Rapraeger,AC
影响因子：
3.2
作者：
Rousseau C;Ruellan AL;Bernardeau K;Kraeber-Bodéré F;Gouard S;Loussouarn D;Saï-Maurel C;Faivre-Chauvet A;Wijdenes J;Barbet J;Gaschet J;Chérel M;Davodeau F
通讯作者：
Davodeau F