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A Specific Inhibitor of TGF-β Receptor Kinase, SB-431542, as a Potent Antitumor Agent for Human Cancers
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Small molecule inhibitors of signaling pathways have proven to be extremely useful for the development of therapeutic strategies for human cancers. Blocking the tumor-promoting effects of transforming growth factor-beta (TGF-beta) in advanced stage carcinogenesis provides a potentially interesting drug target for therapeutic intervention. Although very few TGF-beta receptor kinase inhibitors (TRKI) are now emerging in preclinical studies, nothing is known about how these inhibitors might regulate the tumor-suppressive or tumor-promoting effects of TGF-beta, or when these inhibitors might be useful for treatment during cancer progression. We have investigated the potential of TRKI in new therapeutic approaches in preclinical models. Here, we demonstrate that the TRKI, SB-431542, inhibits TGF-beta-induced transcription, gene expression, apoptosis, and growth suppression. We have observed that SB-431542 attenuates the tumor-promoting effects of TGF-beta, including TGF-beta-induced EMT, cell motility, migration and invasion, and vascular endothelial growth factor secretion in human cancer cell lines. Interestingly, SB-431542 induces anchorage independent growth of cells that are growth-inhibited by TGF-beta, whereas it reduces colony formation by cells that are growth-promoted by TGF-beta. However, SB-431542 has no effect on a cell line that failed to respond to TGF-beta. This represents a novel potential application of these inhibitors as therapeutic agents for human cancers with the goal of blocking tumor invasion, angiogenesis, and metastasis, when tumors are refractory to TGF-beta-induced tumor-suppressor functions but responsive to tumor-promoting effects of TGF-beta.
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“JSH-23 and SB-431542 can suppress NF-κB and TGF-β1/Smad3 signaling pathways respectively and thus might inhibit platelet aggregation in endometriosis91,92.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [92]
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Metadata
- Authors
- Halder, S. K., Beauchamp, R. D., & Datta, P. K.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Datta, Pran K.
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 7
- Issue
- 5
- Pages
- 509-521
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC1501161
- OpenAlex
- W1990842005
- Cited by
- 288
- References
- 37
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 13 · 2023: 9 · 2022: 13 · 2021: 8 · 2020: 16 · 2019: 18 · 2018: 14 · 2017: 11 · 2016: 14 · 2015: 18 · 2014: 18 · 2013: 16 · 2012: 16
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Cancer Research Institute
- GlaxoSmithKline
- Virginia Marine Resources Commission
- National Cancer Institute (R01CA095195, 5P50CA90949, R01CA95195, R01CA069457, CA-69457, P50CA090949)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK52334, R01DK052334)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- SB431542, TGF-beta, anticancer agents, epithelial-mesenchymal transition, tumor invasion, angiogenesis, metastasis, apoptosis, anchorage-independent growth, colony formation, cell motility, vascular endothelial growth factor, TGF-beta signaling
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Animals, Antineoplastic Agents, Benzamides, Cell Adhesion, Cell Line, Cell Movement, Dioxoles, Enzyme Inhibitors, Humans, Mink, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Neovascularization, Pathologic, Time Factors, Transcription, Genetic, Blotting, Western, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Apoptosis, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Activin Receptors, Type I, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Immunoprecipitation, Mice, Rats
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