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

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.

The prognostic significance of protein arginine methyltransferase 6 expression in colon cancer

“…Arginine methylation has been implicated in signal transduction, transcription, mRNA splicing, and DNA damage response, and affects protein-protein interactions and protein localization [ 7 ]. Correspondingly, arginine methylation has been linked to carcinogenesis, metastasis, and drug resistance [ 8 , 9 ], and dysregulation of PRMTs is often associated with diverse types of cancer [ 10 ]. Recently, some PRMTs have emerged as promising targets for cancer therapeutic strategies [ 11 ].…”

Pregnane X Receptor and Cancer: Context-Specificity is Key

“…It is known that PXR undergoes post-translational modifications such as phosphorylation and acetylation (Biswas et al, 2011; Elias et al, 2014; Elias et al, 2013; Pondugula et al, 2015c; Smutny et al, 2013; Staudinger et al, 2011; Sugatani et al, 2015; Wang et al, 2015). In keeping with the same theme, PXR is also regulated at transcriptional and post-transcriptional level (Habano et al, 2011; Kumari et al, 2012; Kumari et al, 2015; Li et al, 2016; Ma et al, 2015; Misawa et al, 2005; Smutny et al, 2013; Takagi et al, 2008; Tian, 2013; Xie et al, 2009). It is possible that some of these modifications may contribute to tissue/context specific PXR activity in tumors.…”

Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

“…Although PXR is expressed mainly in the liver, intestine, and colon tissues, it has been found to be expressed in normal breast tissue, and at even higher levels in breast cancer tissue [ 31 , 36 , 37 , 38 , 39 , 43 ]. In addition, PXR expression has been shown to be induced in breast cancer cell lines MDA-MB-231 and MCF-7 in response to PXR ligand administration [ 46 , 47 ]. Forced overexpression of PXR in these cells resulted in an increased promoter activity and cellular level of drug resistance proteins such as MRP1 and BCRP [ 48 , 49 ].…”

“…When overexpressed, or treated with the PXR agonist, SR12813, PXR reduced the response in breast cancer cells to tamoxifen, cisplatin, and paclitaxel treatment, whereas its downregulation restored cell cycle regulation and apoptosis [ 47 , 48 ]. Li et al, in 2016, provided evidence that the protein arginine methyltransferase 1 (PMRT1), a known epigenetic modifier of histone H4, is an important co-activator of PXR and aids in driving the expression of the MDR1 gene during acquired chemoresistance [ 46 ]. In addition, significant correlations between BCRP expression and resistance to 5-FU treatment has been noted [ 51 ], as well as indications that PXR may modulate a TGF-β induced resistance to chemotherapy in liver cells, via alterations to procaspase-3 and Mcl-1 levels [ 52 ].…”