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First published on July 17, 2007; DOI: 10.1124/mol.107.037937

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Received for publication May 11, 2007.
Revised July 11, 2007.
Accepted for publication July 17, 2007.

Down-regulation of Pregnane X Receptor Contributes to Cell Growth Inhibition and Apoptosis by Anti-cancer Agents in Endometrial Cancer Cells

Hisashi Masuyama 1*, Hideki Nakatsukasa 1, Norio Takamoto 1, Yuji Hiramatsu 1

1 Okayama University Graduate School of Medicine, Dentist and Pharmaceutical Science

* Address correspondence to: E-mail: masuyama{at}cc.okayama-u.ac.jp

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 P-450 3A (CYP3A) family, as well as members of the drug transporter family, including multiple drug resistance 1 (MDR1). Previously, we demonstrated 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 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 anti-cancer 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.


Key words: Sex hormones, MDR/p-Glycoprotein, RNA/siRNA, Resistance


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