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Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes
Open accessAbstract
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.
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Degradation of the Tax protein in the proteasome was observed and subsequently downregulated 5′ viral gene transcription of HTLV-1.
“Notably, the degradation of the Tax protein in the proteasome was observed and subsequently downregulated 5′ viral gene transcription of HTLV-1 [219].”
From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [219]
The Results section reports that niclosamide caused proteasomal degradation of Tax. The Discussion says reduced Tax levels would indirectly lower transcription from the viral 5′-LTR, but presents this as an expected consequence, not an observed transcriptional decrease. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNiclosamide downregulates Tax and pro-survival Bcl-2 proteins to induce apoptosis of HTLV-1-transformed cells.
“Interestingly, niclosamide, which is an anti-helminthic drug approved for the treatment of tapeworms, downregulated Tax and pro-survival Bcl-2 proteins to induce apoptosis of HTLV-1-transformed cells [219].”
From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [219]
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Current State of Therapeutics for HTLV-1
Wang, T. T., Hirons, A., Doerflinger, M., Morris, K. V., Ledger, S., Purcell, D. F. J., Kelleher, A. D., & Ahlenstiel, C. L. (2024) · Viruses · doi:10.3390/v16101616 · Cited by 22
“Treatments for HTLV-1-associated diseases and infection.”
Metadata
- Authors
- Xiang, D., Yuan, Y., Chen, L., Liu, X., Belani, C., & Cheng, H.
- Affiliations
- Penn State Cancer Institute (US)
- Shanghai Jiao Tong University (CN)
- Fujian University of Traditional Chinese Medicine (CN)
- University of Maryland, Baltimore (US)
- Corresponding author
- Cheng, Hua
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 464
- Issue
- 1
- Pages
- 221-228
- ISSN
- 0006-291X (ISSN-L)
- PMC
- PMC4580622
- OpenAlex
- W962365160
- Cited by
- 20
- References
- 2
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI090113)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- niclosamide, HTLV-1, Tax oncoprotein, adult T-cell leukemia/lymphoma, apoptosis, Mcl-1, STAT3, Bcl-2 family proteins, proteasomal degradation, ERK1/2 MAPK, IκB kinase, viral transcription, T-cell transformation
- MeSH terms
- Antinematodal Agents, Cell Line, Transformed, Humans, Niclosamide, T-Lymphocytes, Human T-lymphotropic virus 1, Signal Transduction, Gene Expression Regulation, Viral, Gene Expression Regulation, Neoplastic, Gene Products, tax, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Mitogen-Activated Protein Kinase 1, Proteasome Endopeptidase Complex, Mitogen-Activated Protein Kinase 3, STAT3 Transcription Factor, I-kappa B Kinase, Host-Pathogen Interactions, Proteolysis, Myeloid Cell Leukemia Sequence 1 Protein
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