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.
Keywords:
Down-regulation; HTLV-1; Niclosamide; Tax.
Copyright © 2015 Elsevier Inc. All rights reserved.
MeSH terms
-
Antinematodal Agents / pharmacology*
-
Apoptosis
-
Cell Line, Transformed
-
Gene Expression Regulation, Neoplastic / drug effects*
-
Gene Expression Regulation, Viral / drug effects*
-
Gene Products, tax / antagonists & inhibitors*
-
Gene Products, tax / genetics
-
Gene Products, tax / metabolism
-
Host-Pathogen Interactions / drug effects
-
Human T-lymphotropic virus 1 / drug effects*
-
Human T-lymphotropic virus 1 / genetics
-
Human T-lymphotropic virus 1 / metabolism
-
Humans
-
I-kappa B Kinase / antagonists & inhibitors
-
I-kappa B Kinase / genetics
-
I-kappa B Kinase / metabolism
-
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
-
Mitogen-Activated Protein Kinase 1 / genetics
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
-
Mitogen-Activated Protein Kinase 3 / genetics
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
-
Myeloid Cell Leukemia Sequence 1 Protein / genetics
-
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
-
Niclosamide / pharmacology*
-
Proteasome Endopeptidase Complex / drug effects
-
Proteasome Endopeptidase Complex / metabolism
-
Proteolysis / drug effects
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-bcl-2 / genetics
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
STAT3 Transcription Factor / antagonists & inhibitors
-
STAT3 Transcription Factor / genetics
-
STAT3 Transcription Factor / metabolism
-
Signal Transduction
-
T-Lymphocytes
Substances
-
Antinematodal Agents
-
BCL2 protein, human
-
Gene Products, tax
-
MCL1 protein, human
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Proto-Oncogene Proteins c-bcl-2
-
STAT3 Transcription Factor
-
STAT3 protein, human
-
tax protein, Human T-lymphotrophic virus 1
-
Niclosamide
-
I-kappa B Kinase
-
MAPK1 protein, human
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Proteasome Endopeptidase Complex