| Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. | |
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MedLine Citation:
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PMID: 21159613 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many B-leukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) and in primary CLL cells and was associated with a reduction in serine 727 phosphorylation of STAT3. Similarly, knockdown of STAT3 expression induced apoptosis in these leukemia cells. In addition, we found that JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells. |
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Authors:
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Ganchimeg Ishdorj; James B Johnston; Spencer B Gibson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 3302-14 Citation Subset: IM |
Copyright Information:
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©2010 AACR. |
Affiliation:
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Departments of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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