| Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. | |
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MedLine Citation:
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PMID: 19937797 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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STAT3 activation has been associated with survival, proliferation and invasion of various human cancers. Whether betulinic acid, a pentacyclic triterpene, can modulate the STAT3 pathway, was investigated in human multiple myeloma (MM) cells. We found that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescued betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1 and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the betulinic acid-induced apoptosis. Betulinic acid also enhanced the apoptosis induced by thalidomide (from 10 to 55%) and bortezomib (from 5 to 70%) in MM cells. Overall, our results suggest that betulinic acid downregulates STAT3 activation through upregulation of SHP-1, and this may have potential in sensitization of STAT3 overexpressing tumors to chemotherapeutic agents. |
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Authors:
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Manoj K Pandey; Bokyung Sung; Bharat B Aggarwal |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 127 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-05-26 Completed Date: 2010-06-22 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 282-92 Citation Subset: IM |
Affiliation:
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Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents, Phytogenic
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pharmacology* Apoptosis / drug effects Blotting, Western Boronic Acids / pharmacology Cell Proliferation / drug effects Drug Therapy, Combination Electrophoretic Mobility Shift Assay Enzyme Activation / drug effects Flow Cytometry Humans Immunoenzyme Techniques Immunosuppressive Agents / pharmacology Interleukin-6 / pharmacology Janus Kinase 1 / metabolism Janus Kinase 2 / metabolism Luciferases / metabolism Multiple Myeloma / drug therapy*, metabolism, pathology Protease Inhibitors / pharmacology Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics, metabolism* Pyrazines / pharmacology STAT3 Transcription Factor / genetics, metabolism* Signal Transduction / drug effects* Thalidomide / pharmacology Triterpenes / pharmacology* Tumor Cells, Cultured src-Family Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA124787-020002/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Phytogenic; 0/Boronic Acids; 0/Immunosuppressive Agents; 0/Interleukin-6; 0/Protease Inhibitors; 0/Pyrazines; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Triterpenes; 0/bortezomib; 472-15-1/betulinic acid; 50-35-1/Thalidomide; EC 1.13.12.-/Luciferases; EC 2.7.1.112/JAK1 protein, human; EC 2.7.1.112/JAK2 protein, human; EC 2.7.10.1/Janus Kinase 1; EC 2.7.10.1/Janus Kinase 2; EC 2.7.10.2/src-Family Kinases; EC 3.1.3.48/PTPN6 protein, human; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 6 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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