Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells

Abstract

MicroRNAs are short non-coding RNA molecules able to affect stability and/or translation of mRNA, thereby regulating the expression of genes involved in many biological processes. We report here that microRNAs miR-27a and miR-451 are involved in activating the expression of P-glycoprotein, the MDR1 gene product that confers cancer cell resistance to a broad range of chemotherapeutics. We showed that expressions of miR-27a and miR-451 were up-regulated in multidrug resistant (MDR) cancer cell lines A2780DX5 and KB-V1, as compared with their parental lines A2780 and KB-3-1. Treatment of A2780DX5 cells with the antagomirs of miR-27a or miR-451 decreased the expression of P-glycoprotein and MDR1 mRNA. In contrast, the mimics of miR-27a and miR-451 increased MDR1 expression in the parental cells A2780. The sensitivity to and intracellular accumulation of cytotoxic drugs that are transported by P-glycoprotein were enhanced by the treatment with the antagomirs of miR-27a or miR-451. Our results demonstrate for the first time the roles of microRNAs in the regulation of drug resistance mediated by MDR1/P-glycoprotein, and suggest the potential for targeting miR-27a and miR-451 as a therapeutic strategy for modulating MDR in cancer cells.

The network of P-glycoprotein and microRNAs interactions

“…2 Indeed, several signalling pathways and transcription factors have been described as being involved in the regulation of P-gp expression, such as Wnt=b-catenin, Ras=Raf, MAPK=ERK, p53, NF-jB and PKC. [71][72][73][74][75][76][77] Moreover, several extracellular stimuli such as heat shock, 78 UV radiation, 79 reactive oxygen species 80,81 and cytotoxic drugs 82,83 induce P-gp expression ( Fig. 1-Panel a).…”

“…90 More recently, microRNAs (miRNAs or miRs) have emerged in the literature as regulators of the expression of proteins related to drug resistance, including P-gp. 73 microRNAs as Regulators of P-gp Gene Expression miRs are a class of single-stranded ncRNAs (non-coding RNAs) ranging from 19 to 25 nucleotides in length and having significant roles in gene regulation. The mRNA-miR pairing occurs mostly through the binding of the miR to the target mRNA 3'-UTR; however, binding to the coding region or to the 5'UTR may also occur.…”

“…Therefore, in these cases, the effect of miR-451 in MDR-1 may be indirect, although the precise mechanisms require further investigation. 73 Similarly, miR-27a has also been described as being both a direct and indirect regulator of P-gp. In ovarian and cervical cancer cell lines (A2780 and KB-3-1), MDR-1 mRNA expression was shown to be positively regulated by miR-27a, favoring its role as a possible indirect regulator.…”

“…In ovarian and cervical cancer cell lines (A2780 and KB-3-1), MDR-1 mRNA expression was shown to be positively regulated by miR-27a, favoring its role as a possible indirect regulator. 73 miR-21 is an accepted oncomiR. 133,134 Its expression has been shown to be involved in cellular proliferation, 135,136 apoptosis 135 and autophagy.…”

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

“…It is 17 possible that the miRNA-based therapy could be used to regulate drug sensitivity. For example, the expression changes of miRNA in cancer cells are associated with resistance to anti-cancer drugs (Saker et al, 2010), and there is accumulating evidence that many drug transporters such as MDR1/P-glycoprotein, breast cancer resistance protein (BCRP/ABCG2), and multi-drug resistance-associated protein 1 (MRP1) are regulated by miRNAs (Zhu et al, 2008;Pan et al, 2009b, Liang et al, 2010. It is also possible that miRNAs could be utilized to selectively modulate drug metabolizing enzymes, drug transporters, and nuclear receptors toward optimal drug responses in pharmacotherapy.…”