Protein arginine methyltransferase 1 may be involved in pregnane x receptor-activated overexpression of multidrug resistance 1 gene during acquired multidrug resistant.

Tingting Li,Xuehua Jiang,Zhiqiang Ma,Pinghua Liu,Ling Wang,Ah-Ng Tony Kong,Haiyan Liu,Yu Xiao

doi:10.18632/oncotarget.7752

Abstract

PurposePregnane x receptor (PXR) - activated overexpression of the multidrug resistance 1 (MDR1) gene is an important way for tumor cells to acquire drug resistance. However, the detailed mechanism still remains unclear. In the present study, we aimed to investigate whether protein arginine methyl transferase 1(PRMT1) is involved in PXR - activated overexpression of MDR1 during acquired multidrug resistant.Experimental DesignArginine methyltransferase inhibitor 1 (AMI-1) was used to pharmacologically block PRMT1 in resistant breast cancer cells (MCF7/adr). The mRNA and protein levels of MDR1 were detected by real-time PCR and western blotting analysis. Immunofluorescence microscopy and co-immunoprecipitation were used to investigate the physical interaction between PXR and PRMT1. Then, 136 candidate compounds were screened for PRMT1 inhibitors. Lastly, luciferase reporter gene and nude mice bearing resistant breast cancer xenografts were adopted to investigate the anti-tumor effect of PRMT1 inhibitors when combined with adriamycin.ResultsAMI-1 significantly suppressed the expression of MDR1 in MCF7/adr cells and increased cells sensitivity of MCF7/adr to adriamycin. Physical interaction between PRMT1 and PXR exists in MCF7/adr cells, which could be disrupted by AMI-1. Those results suggest that PRMT1 may be involved in PXR-activated overexpression of MDR1 in resistant breast cancer cells, and AMI-1 may suppress MDR1 by disrupting the interaction between PRMT1 and PXR. Then, five compounds including rutin, isoquercitrin, salvianolic acid A, naproxen, and felodipline were identified to be PRMT1 inhibitors. Finally, those PRMT1 inhibitors were observed to significantly decrease MDR1 promoter activity in vitro and enhance the antitumor effect of adriamycin in nude mice that bearing resistant breast cancer xenografts.ConclusionsPRMT1 may be an important co-activator of PXR in activating MDR1 gene during acquired resistance, and PRMT1 inhibitor combined with chemotherapy drugs may be a new strategy for overcoming tumor MDR.

Highlights

Multidrug resistance (MDR) is a major limiting factor to successful chemotherapy in a variety of cancers [1, 2]
Physical interaction between Protein arginine methyltransferase 1 (PRMT1) and Pregnane x receptor (PXR) exists in MCF7/adr cells, which could be disrupted by Arginine methyltransferase inhibitor 1 (AMI-1)
PRMT1 may be an important co-activator of PXR in activating multidrug resistance 1 (MDR1) gene during acquired resistance, and PRMT1 inhibitor combined with chemotherapy drugs may be a new strategy for overcoming tumor MDR

Summary

Introduction

Multidrug resistance (MDR) is a major limiting factor to successful chemotherapy in a variety of cancers [1, 2]. The mechanisms by which tumor cells acquire overexpressed P-gp have not been clearly characterized. Tumor cells can be induced to acquire MDR by incubating with anticancer drugs either at low concentrations with persistent exposure or at high concentrations with intermittent exposure [8]. Pharmacological inhibition or genetic knockdown of PXR attenuates drug-stimulated MDR1 overexpression and reverses drug resistance [9,10]. It is likely that chemotherapeutic agents stimulate MDR1 overexpression in a PXR-activation pathway. A large number of traditional chemotherapy drugs, such as adriamycin, paclitaxel, microtubule-stabilizing agents, and small molecule tyrosine kinase inhibitors, are exogenous ligands of PXR [13, 14]. It is possible that the binding of these chemotherapy agents and PXR is the initial step for acquired resistance in tumors

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