当前位置: X-MOL 学术Xenobiotica › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Modulation of ABCG2 surface expression by Rab5 and Rab21 to overcome multidrug resistance in cancer cells.
Xenobiotica ( IF 1.3 ) Pub Date : 2020-01-22 , DOI: 10.1080/00498254.2020.1716107
Maryam Yousaf 1 , Moazzam Ali 1
Affiliation  

  1. Human ABCG2 is a half transporter implicated in drug efflux and development of multidrug resistance (MDR) in cancer cells. Here we present the regulatory effects of early endocytic Rab GTPases, Rab5A and Rab21 on ABCG2.

  2. ABCG2 was stably expressed in MCF-7 cells (MCF-7/G2). Rab5A and Rab21 were manipulated in MCF-7/G2 cells by co-expression or siRNA knockdown and their effect on ABCG2-mediated drug efflux was quantified using fluorescence microscopy.

  3. The ectopically expressed ABCG2 was predominantly confined to the plasma membrane and was capable of drug efflux. Expression of constitutively active Rab5A-Q79L mutant in MCF-7/G2 cells decreased the cell surface expression of ABCG2, resulting in the reduction of ABCG2-mediated drug efflux. In contrast, expression of inactive Rab5A-S34N mutant enhanced cell surface expression of ABCG2 and drug efflux. Moreover, reduction in endogenous Rab21 levels in MCF-7/G2 cells by siRNA knockdown, increased the surface localisation of ABCG2. Consequently, efflux ability of cells increased and intracellular retention of doxorubicin and Hoechst 33342; substrates of ABCG2, decreased significantly.

  4. These findings suggest that Rab5A and Rab21 play important roles in regulating ABCG2 surface localisation and turnover and can be exploited as a potential strategy to overcome MDR in cancer cells.



中文翻译:

Rab5和Rab21对ABCG2表面表达的调节,以克服癌细胞中的多药耐药性。

  1. 人ABCG2是一种半转运蛋白,与癌细胞中的药物外流和多药耐药性(MDR)的发生有关。在这里,我们介绍了早期内吞Rab GTPases,Rab5A和Rab21对ABCG2的调节作用。

  2. ABCG2在MCF-7细胞(MCF-7 / G2)中稳定表达。通过共表达或siRNA抑制在MCF-7 / G2细胞中操纵Rab5A和Rab21,并使用荧光显微镜法定量其对ABCG2介导的药物外排的作用。

  3. 异位表达的ABCG2主要局限于质膜,并且能够进行药物外排。组成性活性Rab5A-Q79L突变体在MCF-7 / G2细胞中的表达降低了ABCG2的细胞表面表达,从而导致ABCG2介导的药物外排减少。相反,无活性的Rab5A-S34N突变体的表达增强了ABCG2的细胞表面表达和药物外排。此外,通过siRNA敲低MCF-7 / G2细胞内源Rab21水平的降低,增加了ABCG2的表面定位。因此,细胞的外排能力增加并且阿霉素和Hoechst 33342的细胞内滞留;ABCG2的底物显着下降。

  4. 这些发现表明,Rab5A和Rab21在调节ABCG2表面定位和更新中起重要作用,可以被用作克服癌细胞中MDR的潜在策略。

更新日期:2020-01-22
down
wechat
bug