| Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. | |
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MedLine Citation:
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PMID: 22189713 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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A distinct group of breast cancers, called "basal" or "triple-negative" (TN) cancers express both basal cytokeratins and the epidermal growth factor receptor, but fail to express estrogen receptors, progesterone receptors or HER2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemo-resistant, with p53 mutation, up-regulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin's effects were also studied in sublines with forced over-expression of constitutively active (CA) Stat3, as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin's efficacy in the clinical setting. |
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Authors:
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Xin-Sheng Deng; Shuiliang Wang; Anlong Deng; Bolin Liu; Susan M Edgerton; Stuart E Lind; Reema Wahdan-Alaswad; Ann D Thor |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-15 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 11 ISSN: 1551-4005 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2011-12-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pathology; University of Colorado Denver; Denver, CO USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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