ABC转运蛋白在SPC-A1细胞系中SP细胞多药耐药机制的研究

The mechanism of the role of ABC transporters in the multi-drug resistance of SP cells in SPC-A1 cell lines

目的:近期研究表明,肿瘤是由异质细胞构成的一个群体,肿瘤的形成及生长是由称为肿瘤干细胞的一小群细胞驱动的。由于肿瘤干细胞高表达ABC转运蛋白、通常处于静止期并具有高度的DNA修复能力及抗凋亡能力因而对传统的放化疗耐药。文中研究ABC转运蛋白与SPC-A1细胞系多药耐药及肿瘤干细胞之间的关系。方法:在实验前期构建多西他赛耐药细胞系SPC-A1/Docetaxel的基础上,比较了SPC-A1及SPC-A1/Docetaxel细胞系之间SP细胞的含量及其生物学特性、ABC转运蛋白的表达及其对多西他赛耐药性的影响。结果:SPC-A1及SPC-A1/Docetaxel细胞株中均存在SP细胞,SPC-A1/Docetaxel细胞株中的SP细胞比例高于SPC-A1细胞;耐药蛋白P-gp及乳腺癌耐药蛋白(BCRP)在SPC-A1/Docetaxel细胞株及SPC-A1/Docetaxel-SP细胞中均有明显的表达,而在SPC-A1细胞株的SP细胞中仅BCRP的表达增高;SPC-A1-SP细胞的增殖率、克隆形成能力及致瘤性均显著高于SPC-A1/Docetaxel-SP细胞;SPC-A1/Docetaxel细胞的耐药性可被维拉帕米逆转,而相同浓度的维拉帕米不能完全逆转SPC-A1-SP细胞的Docetaxel耐药。结论:耐药蛋白BCRP在分选人肺腺癌细胞株SPC-A1中具有肿瘤干细胞性质的SP细胞时起主要作用,由此分选的SPC-A1-SP细胞基本具备了肿瘤干细胞的特性,而且BCRP表达也是SPC-A1-SP细胞多西他赛耐药的一个主要因素。

Objective ： Recent researches suggest that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability of maintaining tumor formation/growth specifically resides in a small population of cells called cancer stem cells （CSCs）. CSCs are resistant to traditional cancer chemotherapy and radiation therapy because they highly express ATP-binding cassette （ABC） drug transporters and are relatively quiescent, with higher DNA repair and anti-apoptosis abilities. The purpose of this study is to investigate the relationship of ABC transporters with the multi-drug resistance and cancer stem cells of SPC-A1 cell lines. Methods ： On the basis of Docetaxel-resistant cell line-SPC-A1/Docetaxel, we compared the content and biological characteristics of SP cells, the expression of ABC transporters and its effect on the multi-resistance to Docetaxel between SPC-A1 and SPC-A1/ Docetaxel cell lines. Results： SP cells existed in both the SPC-A1 and the SPC-A1/ Docetaxel cell line, with a higher content in the latter. P-gp and BCRP obviously expressed in the SPC-A1/ Docetaxel and SPC-A1/ Docetaxel-SP cells, but only the expression of BCRP was increased in SPC-A1-SP cells. SPC-A1-SP cells also showed obviously higher abilities of proliferation, cloning and tumor formation than SPC-A1/ Docetaxel-SP cells. The multi-drug resistance of SPC- A1/ Docetaxel cells could be reversed with verapamil, but their resistance to Docetaxel could not be reversed completely with the same concentration of the drug. Conclusion ： BCRP plays a major role in separating SP cells with tumor stem cell traits and its expression counts for the multi-drug resist- ance of SPC-A1-SP cells.