| Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH. | |
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MedLine Citation:
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PMID: 22117045 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The MUC1-C oncoprotein is aberrantly expressed in most multiple myeloma cells. However, the functional significance of MUC1-C expression in multiple myeloma is not known. The present studies demonstrate that treatment of multiple myeloma cells with a MUC1-C inhibitor is associated with increases in reactive oxygen species (ROS), oxidation of mitochondrial cardiolipin, and loss of the mitochondrial transmembrane potential. The MUC1-C inhibitor-induced increases in ROS were also associated with down-regulation of the p53-inducible regulator of glycolysis and apoptosis (TIGAR). In concert with the decrease in TIGAR expression, which regulates the pentose phosphate pathway, treatment with the MUC1-C inhibitor reduced production of NADPH, and in turn glutathione (GSH) levels. TIGAR protects against oxidative stress-induced apoptosis. The suppression of TIGAR and NADPH levels thus contributed to ROS-mediated late apoptosis/necrosis of multiple myeloma cells. These findings indicate that multiple myeloma cells are dependent on MUC1-C and TIGAR for maintenance of redox balance and that targeting MUC1-C activates a cascade involving TIGAR suppression that contributes to multiple myeloma cell death. |
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Authors:
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Li Yin; Michio Kosugi; Donald Kufe |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-11-23 |
Journal Detail:
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Title: Blood Volume: 119 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-01-20 Completed Date: 2012-03-13 Revised Date: 2012-04-16 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 810-6 Citation Subset: AIM; IM |
Affiliation:
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Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Apoptosis* Blotting, Western Cardiolipins / metabolism Cell Line, Tumor Down-Regulation Humans Intracellular Signaling Peptides and Proteins / antagonists & inhibitors, genetics, metabolism* Membrane Potential, Mitochondrial Mitochondria / metabolism Mucin-1 / chemistry*, genetics, metabolism* Multiple Myeloma / metabolism*, pathology* NADP / metabolism* Necrosis Oxidation-Reduction Oxidative Stress RNA, Messenger / genetics RNA, Small Interfering / genetics Reactive Oxygen Species / metabolism Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction |
| Grant Support | |
ID/Acronym/Agency:
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CA42802/CA/NCI NIH HHS; R01 CA042802-25/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/C12orf5 protein, human; 0/Cardiolipins; 0/Intracellular Signaling Peptides and Proteins; 0/MUC1 protein, human; 0/Mucin-1; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 53-59-8/NADP; 56-65-5/Adenosine Triphosphate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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