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Title: Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes

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. - Highlights: • Niclosamide is a promising therapeutic candidate for adult T cell leukemia. • Niclosamidemore » employs a novel mechanism through proteasomal degradation of Tax. • Niclosamide downregulates certain cellular pro-survival molecules.« less
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [4] ; ;  [1] ;  [5] ;  [4] ;  [4] ;  [4]
  1. Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033 (United States)
  2. (China)
  3. Pharmacy College, Fujian University of Traditional Chinese Medicine, Fuzhou (China)
  4. (United States)
  5. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 (United States)
Publication Date:
OSTI Identifier:
22462184
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 464; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BORON CHLORIDES; GENES; HUMAN POPULATIONS; LEUKEMIA; LEUKEMIA VIRUSES; LYMPHOCYTES; LYMPHOMAS; MOLECULES; PHOSPHOTRANSFERASES; PLANT GROWTH; SIGNALS; TAXES; TRANSCRIPTION; TRANSFORMATIONS