|Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells.|
|PMID: 19937797 Owner: NLM Status: MEDLINE|
|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.|
|Manoj K Pandey; Bokyung Sung; Bharat B Aggarwal|
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|Type: Journal Article|
|Title: International journal of cancer. Journal international du cancer Volume: 127 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2010 Jul|
|Created Date: 2010-05-26 Completed Date: 2010-06-22 Revised Date: 2014-04-08|
Medline Journal Info:
|Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States|
|Languages: eng Pagination: 282-92 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Antineoplastic Agents, Phytogenic
Apoptosis / drug effects
Boronic Acids / pharmacology
Cell Proliferation / drug effects
Drug Therapy, Combination
Electrophoretic Mobility Shift Assay
Enzyme Activation / drug effects
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
|P01 CA124787/CA/NCI NIH HHS; P01 CA124787-020002/CA/NCI NIH HHS|
|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; 4G6A18707N/betulinic acid; 4Z8R6ORS6L/Thalidomide; EC 1.13.12.-/Luciferases; EC 2.7.010.2/JAK1 protein, human; EC 22.214.171.124/JAK2 protein, human; EC 126.96.36.199/Janus Kinase 1; EC 188.8.131.52/Janus Kinase 2; EC 184.108.40.206/src-Family Kinases; EC 220.127.116.11/PTPN6 protein, human; EC 18.104.22.168/Protein Tyrosine Phosphatase, Non-Receptor Type 6|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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