Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China.
J Pharmacol Sci. 2013;122(4):299-304. doi: 10.1254/jphs.13025fp. Epub 2013 Aug 1.
Multiple drug resistance (MDR) occurring during chemotherapy is a major obstacle for treatment of cancers using chemotherapeutic drugs; thus, the mechanisms underlying MDR have attracted intensive attention. Many studies have shown that tumor-initiating cells exhibit a chemotherapeutic tolerance characteristic. However, whether the MDR cells possess tumor-initiating cells properties and its underlying mechanisms remain to be fully elucidated. In this study, we utilized a well-established MDR cell line K562/A02 enriched by doxorubicin from K562 cells to determine if the K562/A02 cells possess tumor-initiating properties and investigated its potential molecular mechanisms. We observed that the expressions of Oct4, Sox2, and Nanog, all of which are well-characterized stem cell markers, in K562/A02 cells were elevated in comparison to parental K562 cells; in addition, we found that K562/A02 cells exhibited more potent in vitro and in vivo tumor-initiating properties, as revealed by sphere assay, self-renewal assay, soft agar assay, and animal studies. Furthermore, our data suggest that snail and twist1, two well known transcriptional factors for the epithelial-mesenchymal transition (EMT) program, may be potentially involved in the acquisition of tumor-initiating properties of K562/A02 cells. Thus, our study demonstrates that MDR K562/A02 cells possess tumor-initiating properties, most likely due to the elevated expressions of snail and twist1.
多药耐药（MDR）在化疗过程中发生，是使用化疗药物治疗癌症的主要障碍；因此，MDR 的机制引起了广泛关注。许多研究表明，肿瘤起始细胞表现出化疗耐受性特征。然而，MDR 细胞是否具有肿瘤起始细胞特性及其潜在机制仍有待充分阐明。在这项研究中，我们利用阿霉素从 K562 细胞中富集的已建立的 MDR 细胞系 K562/A02，来确定 K562/A02 细胞是否具有肿瘤起始特性，并研究其潜在的分子机制。我们观察到，与亲本 K562 细胞相比，K562/A02 细胞中 Oct4、Sox2 和 Nanog 的表达升高，这三种蛋白均为特征明确的干细胞标志物；此外，我们发现 K562/A02 细胞表现出更强的体外和体内肿瘤起始特性，球体形成实验、自我更新实验、软琼脂实验和动物研究均证实了这一点。此外，我们的数据表明，Snail 和 Twist1，两种上皮-间充质转化（EMT）程序的已知转录因子，可能参与了 K562/A02 细胞获得肿瘤起始特性。因此，我们的研究表明，MDR K562/A02 细胞具有肿瘤起始特性，这可能是由于 Snail 和 Twist1 的表达升高。
