A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways
A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways
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DOI：
10.1158/0008-5472.can-10-1303
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Yi-Ching
中科院分区：
文献类型：
--
作者：
Chen, Jia-Yang;Tang, Yen-An;Wang, Yi-Ching
唾液酸转移酶(ST)活性增强促进癌细胞转移，细胞表面唾液酸过度表达与癌症患者预后不良相关。为了寻找针对肿瘤转移的治疗方法，我们开发了一种新的ST抑制剂Lith-O-Asp，并研究了其抗肿瘤转移和抗血管生成的作用及其机制。通过体外和基于细胞的活性分析，我们发现Lith-O-Asp处理的细胞对各种ST酶的活性降低。Lith-O-Asp抑制多种肿瘤细胞的迁移和侵袭能力，并对人脐静脉内皮细胞的血管生成活性具有抑制作用。事实上，在实验和动物模型的自发转移试验中，Lith-O-Asp治疗结果延缓了癌细胞的转移。重要的是，Lith-O-Asp减少了整合素-β1的唾液酸修饰，并抑制了磷酸化FAK、磷酸化PXLIN以及基质金属蛋白酶(MMP2)和MMP9的表达。Lith-O-Asp可减弱Rho GTP酶活性，导致肌动蛋白动态损伤。此外，2DE-MS/MS和免疫印迹分析表明，Lith-O-Asp改变了与肿瘤转移和血管生成途径有关的各种蛋白的蛋白表达水平和磷酸化状态，如波形蛋白和核糖核酸酶/血管生成抑制物RNH1。此外，Lith-O-Asp处理显著抑制了催化α-2，6-或α-2，3-唾液酸化的各种ST酶的异位过表达所产生的侵袭能力。我们的结果提供了令人信服的证据，潜在的PAN-ST抑制剂Lith-O-Asp可能通过抑制FAK/paxlin信号转导和表达抗血管生成因子来抑制癌细胞的转移。Lith-O-Asp是一种新型的抗肿瘤转移药物，值得进一步研究。癌症资源；71(2)；473-83。(C)2011年AACR。
Increased sialyltransferase (ST) activity promotes cancer cell metastasis, and overexpression of cell surface sialic acid correlates with poor prognosis in cancer patients. To seek therapies targeting metastasis for cancer treatment, we developed a novel ST inhibitor, Lith-O-Asp, and investigated its antimetastatic and antiangiogenic effects and mechanisms. We found that cells treated with Lith-O-Asp showed a reduction of activity on various ST enzymes by in vitro and cell-based activity analyses. Lith-O-Asp inhibited migration and invasion abilities in various cancer cell lines and showed inhibitory effect on the angiogenic activity of human umbilical vein endothelial cells. Indeed, Lith-O-Asp treatment consequently delayed cancer cell metastasis in experimental and spontaneous metastasis assays in animal models. Importantly, Lith-O-Asp decreased the sialic acid modification of integrin-beta 1 and inhibited the expression of phospho-FAK, phospho-paxillin, and the matrix metalloprotease (MMP) 2 and MMP9. Lith-O-Asp attenuated the Rho GTPase activity leading to actin dynamic impairment. In addition, 2DE-MS/MS and immunoblotting analyses showed that Lith-O-Asp altered the protein expression level and phosphorylation status of various proteins involved in crucial metastasis and angiogenesis pathways such as vimentin and ribonuclease/angiogenin inhibitor RNH1. Furthermore, Lith-O-Asp treatment significantly inhibited the invasive ability exerted by ectopic overexpression of various ST enzymes catalyzing alpha-2,6- or alpha-2,3-sialylation. Our results provide compelling evidence that the potential pan-ST inhibitor, Lith-O-Asp, suppressed cancer cell metastasis likely by inhibiting FAK/paxillin signaling and expressing antiangiogenesis factors. Lith-O-Asp is worthy for further testing as a novel antimetastasis drug for cancer treatment. Cancer Res; 71(2); 473-83. (C) 2011 AACR.