WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells.

Hwang Hwang,Won Won,Choi Choi,Lee Lee,Pham Pham,Jin Jin,Kang Kang,Jeong Jeong

doi:10.3390/ijms20235928

Abstract

Human cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endobiotics and xenobiotics plays an important role in the progression of human breast cancer. In this study, we investigated the effects of WY-14643, a peroxisome proliferator-activated receptor α (PPARα) agonist, on CYP1B1 expression and the related mechanism in MCF7 breast cancer cells. We performed quantitative reverse transcription-polymerase chain reaction, transient transfection, and chromatin immunoprecipitation to evaluate the effects of PPARα on peroxisome proliferator response element (PPRE)-mediated transcription. WY-14643 increased the protein and mRNA levels of CYP1B1, as well as promoter activity, in MCF-7 cells. Moreover, WY-14643 plus GW6471, a PPARα antagonist, significantly inhibited the WY-14643-mediated increase in CYP1B1 expression. PPARα knockdown by a small interfering RNA markedly suppressed the induction of CYP1B1 expression by WY-14643, suggesting that WY-14643 induces CYP1B1 expression via a PPARα-dependent mechanism. Bioinformatics analysis identified putative PPREs (−833/−813) within the promoter region of the CYP1B1 gene. Inactivation of these putative PPREs by deletion mutagenesis suppressed the WY-14643-mediated induction of CYP1B1 promoter activation. Furthermore, WY-14643 induced PPARα to assume a form capable of binding specifically to the PPRE-binding site in the CYP1B1 promoter. Our findings suggest that WY-14643 induces the expression of CYP1B1 through activation of PPARα.

Highlights

Breast cancer is the most common cancer in women and the second most common cause of cancer-related death in women worldwide [1]
We demonstrate that the expression of cytochrome P450 1B1 (CYP1B1) is highly induced by the peroxisome proliferator-activated receptor α (PPARα) agonist, WY-14643, in a manner involving the transcription factor PPARα and requiring peroxisome proliferator response element (PPRE) sites located within the CYP1B1 promoter
To examine whether the induction of CYP1B1 by WY-14643 is mediated by a PPARα-dependent pathway, we investigated the effect of GW6471, a PPARα antagonist, on WY-14643-induced expression of CYP1B1

Summary

Introduction

Breast cancer is the most common cancer in women and the second most common cause of cancer-related death in women worldwide [1]. Cytochromes P450 (CYPs) are hemoproteins involved in the metabolism and degradation of several endogenous compounds, including estradiol and fatty acids. They are involved in the bioactivation of environmental procarcinogens, such as arylamines and polycyclic aromatic hydrocarbons. CYP1B1 is presumed to be essential for the initiation and development of various hormone-dependent tumors, including breast cancer, through the biotransformation of endogenous estrogens and environmental carcinogens [4]. The 17-β-estradiol-2,3-semiquinones derived from 2-hydroxyestradiol produce stable and less harmful DNA adducts [6] Based on these observations, inhibition of CYP1B1, an important drug target, has been proposed as a therapeutic strategy for breast cancer [5]

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Results

Conclusion