title: Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1.
abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the basic helix-loop-helix PER/ARNT/SIM family of chemosensors and developmental regulators. The AhR is widely known as a mediator of dioxin toxicity; however, it also suppresses cancer cell proliferation and recent findings have implicated its role as a tumor suppressor. We conducted a chemical library screen to identify nontoxic AhR ligands with anti-cancer effects and discovered flutamide (Eulexin) as a putative AhR ligand. Flutamide is an androgen receptor (AR) antagonist approved by the United States Food and Drug Administration for the treatment of prostate cancer. We found that flutamide inhibited the growth of several cancer cell lines independent of AR status, and that suppression of AhR expression reversed the anti-proliferative effects of flutamide. We investigated the AhR-dependent mechanism of action of flutamide in human hepatocellular carcinoma cells and identified that transforming growth factor-β1 (TGF-β1) is induced by flutamide in an AhR-dependent manner. In contrast, the potent AhR agonist 2,3,7,8-Tetrachlorodibenzo-p-dioxin had no effect on TGF-β1 expression, indicating the ligand specificity of AhR activation. We also determined that TGF-β1 induction is required for the AhR-dependent growth inhibitory effects of flutamide. Therefore, flutamide may be effective in AhR-positive cancers that are sensitive to TGF-β1 signaling, such as hepatocellular carcinoma.
authors: Department of Environmental and Molecular Toxicology, Cancer Research Laboratory, Oregon State University, Corvallis, OR, USA.|Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: D C
authors: DC
authors: Koch
authors: Department of Environmental and Molecular Toxicology, Cancer Research Laboratory, Oregon State University, Corvallis, OR, USA.|Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: H S
authors: HS
authors: Jang
authors: Department of Environmental and Molecular Toxicology, Cancer Research Laboratory, Oregon State University, Corvallis, OR, USA.|Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: E F
authors: EF
authors: O'Donnell
authors: Department of Environmental and Molecular Toxicology, Cancer Research Laboratory, Oregon State University, Corvallis, OR, USA.|Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: S
authors: S
authors: Punj
authors: Department of Environmental and Molecular Toxicology, Cancer Research Laboratory, Oregon State University, Corvallis, OR, USA.|Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: P R
authors: PR
authors: Kopparapu
authors: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: W H
authors: WH
authors: Bisson
authors: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: N I
authors: NI
authors: Kerkvliet
authors: Department of Environmental and Molecular Toxicology, Cancer Research Laboratory, Oregon State University, Corvallis, OR, USA.|Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR, USA.
authors: S K
authors: SK
authors: Kolluri
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D005485:Flutamide / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D000726:Androgen Antagonists; D018336:Receptors, Aryl Hydrocarbon; D053773:Transforming Growth Factor beta1; D005485:Flutamide