The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells

Abstract

Resistance to anticancer drugs is often mediated by the overexpression of P-glycoprotein encoded by the multi-drug resistance (MDR1) gene. The nuclear receptor, steroid and xenobiotic receptor (SXR), is one of the key transcriptional regulators of MDR1 gene expression. A variety of xenobiotics bind to SXR, and stimulate transcription on xenobiotic-response elements (XREs), located in the MDR1 gene promoter. Diethylhexyl phthalate (DEHP) is widely used as a plasticizer for polyvinyl chloride (PVC) medical devices. Previous studies have shown that a significant amount of DEHP leaches from PVC infusion bags and lines during interventions, such as total parenteral nutrition, blood transfusion, and cancer chemotherapy. Thus, the leaching of DEHP during parenteral chemotherapy for cancer patients may facilitate MDR1 expression in various tissues, including cancer cells, which may promote drug resistance. To examine such a hypothesis, the effect of DEHP on SXR-mediated transcription of the MDR1 gene was studied in the human colon adenocarcinoma-derived cell line, LS174T cells, which endogenously express SXR. DEHP increased the SXR-mediated transcription of the MDR1 gene in luciferase-reporter assays. The induction by DEHP was abrogated when a reporter plasmid containing mutated DRC4 motif in the XRE was used. In a mammalian two-hybrid assay, DEHP recruited steroid receptor co-activator-1 to the ligand-binding domain of SXR. Finally, using real-time reverse transcriptase-PCR, we showed that DEHP increased MDR1 gene expression in a dose-dependent manner. We conclude that DEHP is an inducer of the MDR1 gene in this cell line. As such, the leaching of DEHP from the PVC medical devices may influence the MDR1 expression, which may induce resistance to drugs in certain populations of cancer cells.

Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor

“…Human SXR, GAL4 steroid receptor coactivator 1 (SRC1)-receptor-interacting domain (RID), VP16 SXR-ligandbinding domain (LBD), and VP16 SXR-DAF2 LBD expression plasmids were described previously (Takeshita et al 2006(Takeshita et al , 2011. The luciferase (LUC) reporter construct, 5X upstream activating sequence (UAS)-thymidine kinase minimum promoter (TK)-LUC (Cohen et al 2000), and xenobiotic-responsive enhancer module (XREM)-CYP3A4-LUC (Goodwin et al 1999) were described previously.…”

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

“…Since incurable cancer, which afflicts over 450 persons per 100,000 annually, is a growing health epidemic, it is important to establish a relationship between environmental xenogens (i.e., endocrine disruptors) and cancer (30). Indeed, recent studies on this subject indicate a growing correlation between high exposure to endocrine disruptors (e.g., bisphenol A, xenoestrogens, polycyclic aromatic hydrocarbons) and cancer risk or drug response (13,(31)(32)(33)(34)(35)(36)(37). The question is particularly relevant given that recent developments in cancer drug therapy (e.g., targeted therapy) are markedly improving survivability.…”

“…Simultaneously, over the last several decades, our burden of environmental xenotoxins has increased substantially. Recent work implicates several xenogens in cancer cell growth and drug resistance (13,(31)(32)(33)(34)(35)(36)(37). Indeed, the molecular pathways governing the tissue-specific phenotypes mediated by chronic exposure to endocrine disruptors are varied, and it is clear that some important effects are mediated via nuclear receptors.…”

Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites

“…A small sample of the molecules published and suggested to bind PXR include: bile salts (Schuetz and Strom, 2001;Krasowski et al, 2005a), cholesterol and its metabolites (Sonoda et al, 2005), statins (El-Sankary et al, 2001), endocrine disruptors (Takeshita et al, 2001(Takeshita et al, , 2006, synthetic peptide bond mimetics (Mu et al, 2005), anticancer compounds (Mani et al, 2005), herbal components and plant extracts Ding and Staudinger, 2005;Mu et al, 2006), carotenoids (Rü hl et al, 2004(Rü hl et al, , 2005, vitamins , HIV protease inhibitors , calcium channel modulators (Drocourt et al, 2001), steroids , plasticizers (Masuyama et al, 2000(Masuyama et al, , 2002Takeshita et al, 2001), pesticides (Coumol et al, 2002;Lemaire et al, 2004), peroxisome proliferator-activated receptor-␥ antagonists (Leesnitzer et al, 2002), as well as other diverse xenobiotics and endobiotics (Lehmann et al, 1998;Waxman, 1999;Ekins and Erickson, 2002;Luo et al, 2002;Schuster et al, 2006;Ung et al, 2007), including agonists for additional nuclear receptors (Xue et al, 2007a).…”