title: Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.
abstract: Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells.
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033.
authors.forename: Di
authors.initials: D
authors.lastname: Xiang
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033.|Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Pharmacy College, Fujian University of Traditional Chinese Medicine, Fuzhou, China.|Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033.
authors.forename: Chandra
authors.initials: C
authors.lastname: Belani
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000969:Antinematodal Agents / Q000494:pharmacology*; D017209:Apoptosis; D002461:Cell Line, Transformed; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016356:Gene Products, tax / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes
chemical_list: D000969:Antinematodal Agents; C000595707:BCL2 protein, human; D016356:Gene Products, tax; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C514970:tax protein, Human T-lymphotrophic virus 1; D009534:Niclosamide; D051550:I-kappa B Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: Down-regulation; HTLV-1; Niclosamide; Tax