Abstract
Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of drug-metabolizing enzymes, cytochrome P450 3A (CYP3A) family, and members of the drug transporter family, including multiple drug resistance 1 (MDR1). We demonstrated previously that steroid/xenobiotic metabolism by tumor tissue through the PXR-CYP3A pathway might play an important role in endometrial cancer and that PXR ligands enhance PXR-mediated transcription in a ligand- and promoter-dependent fashion, leading to differential regulation of individual PXR targets, especially CYP3A4 and MDR1. In this study, we investigated the potential contribution of PXR down-regulation by RNA interference toward the augmentation of drug sensitivity and the overcoming of drug resistance. We observed the protein levels of both CYP3A4 and MDR1 in PXR small interfering RNA (siRNA)-transfected cells were not increased in the presence of PXR ligands, paclitaxel, cisplatin, estradiol, or medroxyprogesterone acetate (MPA) compared with control siRNA-transfected cells. There was no PXR-mediated transactivation or augmentation of transcription by coactivators in the presence of these ligands. We then found that PXR down-regulation caused a significant increase in cell growth inhibition and enhancement of apoptosis in the presence of the anticancer agents, paclitaxel, cisplatin, and MPA. Finally, we demonstrated that PXR overexpression caused a significant decrease in cell growth inhibition and inhibited apoptosis in the presence of paclitaxel or cisplatin. These data suggest that PXR down-regulation could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance to them, in the treatment of endometrial cancer.
Footnotes
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This work was supported in part by research grants (17591739) from the Ministry of Education, Science, and Culture of Japan and the Okayama Medical Foundation (to H.M.)
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.037937.
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ABBREVIATIONS: PXR, pregnane X receptor; PXRE, pregnane X receptor-responsive element; MDR1, multiple drug resistance 1; SRC-1, steroid receptor coactivator-1; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MPA, medroxyprogesterone acetate; estradiol, 17β-estradiol; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; CAT, chloramphenicol acetyl transferase; AIB1, amplified in breast cancer 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; siRNA, small interfering RNA; DMSO, dimethyl sulfoxide; tk, thymidine kinase.
- Received May 10, 2007.
- Accepted July 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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