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

已有研究表明，ARF-GEP100(P100)在体外优先激活ARF(ADP-核糖化因子)，调节多种细胞功能。相比之下，P-糖蛋白(Pgp)能将多种抗癌药物转运出细胞。Pgp的抑制有望绕过Pgp介导的耐药性。在这项研究中，我们使用多柔比星(DOX)耐药的K562细胞检测了P100是否会影响Pgp的表达。P100表达水平升高，并伴有Pgp表达。有趣的是，P100在细胞膜部分的表达增加。此外，抗Pgp抗体在DOX抗性细胞裂解物中免疫沉淀P100。用ARF6 siRNA处理耐药细胞，检测Pgp和P100的表达水平。但Pgp和P100的表达没有改变，提示P100可能参与了Pgp的表达和激活，从而诱导了对阿霉素的耐药性。

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.