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Anti-oral cancer strategy by means of inhibition of cellular adhesion to extracellula matrices

通过抑制细胞与细胞外基质的粘附来抗口腔癌策略

基本信息

批准号：
10557170
负责人：
SAKU Takashi
金额：
$ 8.77万
依托单位：
NIIGATA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557170/
关键词：
extracellular matrix heparan sulfate proteoglycan fibronectin integrin cell adhesion focal adhesion kinase ACC3 anti-cancer strategy スラミン RT-PCR 口腔癌 RGDペプチド

项目摘要

We have analyzed anti-cancer effect in a situation in which adhesion of oral carcinoma cells to extracellular matrices is inhibited. To this end, suramin, a polysulfonated naphthylurea, which has been used as an anti-trypanosoma reagent but has also known as an inhibitor of lysosomal heparanase, was used for inhibition of adhesion of oral carcinoma cells, such as ACC3 cells of human salivary adenoid cystic carcinoma origin.ACC3 cells have been known to biosynthesize excessive amounts of extracellular matrix (ECM) molecules, especially basement membrane-associated molecules, such as heparan sulfate proteoglycan, HSPG/perlecan, and fibronectin. When ACCE cess were cultivated in the presence of 100 ;uM suramin, secretion of ECM molecules by ACC3 cells into the culture medium was enhanced. When 200 fM suramin was added, attachment of ACC3 cells to culture dishes reduced significantly. In the presence of suramin and RGD peptides, which are an ECM recoginition site of integrins, the attachme … More nt was two times more inhibited. Thus, it was suggested that suramin affected integrih-dependent cell adhesion. By day 7 of culture in the presence of suramin, ECM molecules were shed more prominently into the culture medium of ACC3 cells. Immunofluorescence showed that ECM molecules and integrins were localized within the cytoplasm but not in the extracellular space or in the cell surface. These results indicated suramin inhibited cell membrane assembly of integrin and consequently trapping of ECM molecules by cell surface integrins.Immunoprecipitation and pulse-chase experi-ments showed that suramin inhibited biosynthesis of an unknown molecule with Mr. 120 kDa, which was co-precipitated with integrin a5. Immunoblotting experiments showed that the 120 kDa molecule was focal adhesion kinase (FAK), which functions in phospholylation of integrins. The results indicated that suramin inhibit FAK expression of ACC3 cells, which resulted in integrin function in cellular attachment.These results clearly indicate that the inhibition of cell surface receptors for ECM molecules can be one of the strategies for suppression of oral carcinoma cell growth. Less

我们分析了在抑制口腔癌细胞与细胞外基质粘附的情况下的抗癌效果。为此，苏拉明，一种多磺化萘脲，已被用作抗锥虫试剂，但也被称为溶酶体乙酰肝素酶的抑制剂，用于抑制口腔癌细胞的粘附，例如人唾液腺样囊性癌来源的ACC 3细胞。已知ACC 3细胞生物合成过量的细胞外基质（ECM）分子，特别是基底膜相关分子，例如硫酸乙酰肝素蛋白聚糖、HSPG/串珠素和纤连蛋白。当ACCE细胞在100 μ M苏拉明存在下培养时，ACC 3细胞向培养基中分泌ECM分子增强。当加入200 fM苏拉明时，ACC 3细胞对培养皿的附着显著减少。在苏拉明和RGD肽（它们是整联蛋白的ECM结合位点）存在下， ...更多信息 NT是两倍多的抑制。因此，这表明苏拉明影响整合依赖性细胞粘附。到苏拉明存在下培养的第7天，ECM分子更显著地脱落到ACC 3细胞的培养基中。免疫荧光显示，ECM分子和整合素定位在细胞质内，但不在细胞外空间或细胞表面。免疫沉淀和脉冲追踪实验表明，苏拉明抑制了整合素α 5与一个分子量为120 kDa的未知分子的生物合成。免疫印迹实验表明，120 kDa的分子是粘着斑激酶（FAK），其功能在整合素的磷酸化。结果表明，苏拉明抑制ACC 3细胞FAK的表达，从而使整合素在细胞粘附中发挥作用，抑制细胞表面ECM分子的受体可能是抑制口腔癌细胞生长的策略之一。少