Role of a guanine nucleotide-exchange protein, ARF-GEP100, in the doxorubicin resistance of K562 human leukemia cells

已经发现，ARF-GEP 100（p100）在体外优先激活ARF（ADP-核糖基化因子）并调节多种细胞功能。相比之下，P-糖蛋白（Pgp）将广泛的抗癌药物转运出细胞。Pgp的抑制有望规避Pgp介导的耐药性。在本研究中，我们使用阿霉素（DOX）耐药的K562细胞检测p100是否可能影响Pgp的表达。p100蛋白表达增强，同时伴有Pgp表达。有趣的是，p100的表达在细胞膜部分中增加。此外，抗Pgp抗体免疫沉淀p100在DOX耐药细胞裂解液。研究ARF 6 siRNA处理的DOX耐药细胞的Pgp和p100表达水平。Pgp和p100的表达无明显变化，提示p100可能参与了Pgp的表达和激活，从而诱导DOX耐药。

It has been already revealed that ARF-GEP100 (p100) preferentially activates ARF (ADP-ribosylation factor) in vitro and regulated various cell functions. In contrast, P-glycoprotein (Pgp) transports a broad range of anticancer drugs out of the cells. The inhibition of Pgp is expected to circumvent the Pgp-mediated drug resistance. In this study, we examined whether p100 may affect the expression of Pgp using the Doxorubicin (DOX)-resistant K562 cells. The expression level of p100 increased, accompanied with Pgp expression. Interestingly, the expression of p100 was increased in the cell membrane fraction. Furthermore, anti-Pgp antibody immunoprecipitated p100 in DOX resistant cell lysate. The DOX resistant cells treated with ARF6 siRNA were investigated for expression level of Pgp and p100. However, the expression of Pgp and p100 was not changed.Collectively, these observations suggest that p100 may be involved in the expression and activation of Pgp to induce the DOX resistance.