title: 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 DR+4 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.
authors.affiliation: Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato, Tokyo 105-8470, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.forename: Keiji
authors.initials: K
authors.lastname: Inagaki
authors.forename: Junko
authors.initials: J
authors.lastname: Igarashi-Migitaka
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koibuchi
mesh_terms: D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D019450:Genes, MDR; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D010968:Plasticizers / Q000633:toxicity; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection / Q000379:methods; D015262:Xenobiotics
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D010968:Plasticizers; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics; D004051:Diethylhexyl Phthalate; D008156:Luciferases